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Journal articles on the topic 'Glomeruli'
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1
Wang, Honglian, Jingyi Sheng, Huijun He, Xiaocui Chen, Jinhong Li, Ruizhi Tan, Li Wang, and Hui-Yao Lan. "A simple and highly purified method for isolation of glomeruli from the mouse kidney." American Journal of Physiology-Renal Physiology 317, no. 5 (November 1, 2019): F1217—F1223. http://dx.doi.org/10.1152/ajprenal.00293.2019.
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Highly purified mouse glomeruli are of great value for studying glomerulus-associated kidney diseases. Here, we developed a simple and rapid procedure for mouse glomerular isolation with large quantity and high purity based on the combination of size-selective sieving and differential adhesion techniques, which we termed the “differential adhesion method.” In this method, mouse renal cortices were minced and digested with collagenase. Glomeruli were disassociated from tubules by successive sieving through 105-, 75-, and 40-μm cell strainers. The retained glomeruli-rich preparation on the 40-μm strainer was rinsed into a cell culture dish to allow tubules to adhere quickly to the dish while leaving most glomeruli floating (termed “differential adhesion”). The floating glomerular fraction was then subjected to another wash through the 40-μm strainer followed by an additional differential adhesion step to obtain highly purified glomeruli with yields of 8,357 ± 575 and purity of 96.1 ± 1.8% from one adult C57BL/6 mouse. The purity of the isolated glomeruli was further confirmed by high expression of the podocyte marker nephrin without detectable tubular marker cadherin-16. Importantly, we also found that although both the quantity and purity of the isolated glomeruli by this and the established Dynabeads method were comparable, glomeruli isolated by the current method showed much less inflammatory stress in terms of proinflammatory cytokine expression than the Dynabeads method. In conclusion, we established a newly mouse glomerular isolation method that is simple, rapid, cost effective, and productive. It provides an advanced methodology for research into glomerulus-related kidney diseases in the mouse.
2
Beeman, Scott C., Min Zhang, Lina Gubhaju, Teresa Wu, John F. Bertram, David H. Frakes, Brian R. Cherry, and Kevin M. Bennett. "Measuring glomerular number and size in perfused kidneys using MRI." American Journal of Physiology-Renal Physiology 300, no. 6 (June 2011): F1454—F1457. http://dx.doi.org/10.1152/ajprenal.00044.2011.
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The goal of this work was to nondestructively measure glomerular (and thereby nephron) number in the whole kidney. Variations in the number and size of glomeruli have been linked to many renal and systemic diseases. Here, we develop a robust magnetic resonance imaging (MRI) technique based on injection of cationic ferritin (CF) to produce an accurate measurement of number and size of individual glomeruli. High-field (19 Tesla) gradient-echo MR images of perfused rat kidneys after in vivo intravenous injection of CF showed specific labeling of individual glomeruli with CF throughout the kidney. We developed a three-dimensional image-processing algorithm to count every labeled glomerulus. MRI-based counts yielded 33,786 ± 3,753 labeled glomeruli ( n = 5 kidneys). Acid maceration counting of contralateral kidneys yielded an estimate of 30,585 ± 2,053 glomeruli ( n = 6 kidneys). Disector/fractionator stereology counting yielded an estimate of 34,963 glomeruli ( n = 2). MRI-based measurement of apparent glomerular volume of labeled glomeruli was 4.89 × 10−4mm3( n = 5) compared with the average stereological measurement of 4.99 × 10−4mm3( n = 2). The MRI-based technique also yielded the intrarenal distribution of apparent glomerular volume, a measurement previously unobtainable in histology. This work makes it possible to nondestructively measure whole-kidney glomerular number and apparent glomerular volumes to study susceptibility to renal diseases and opens the door to similar in vivo measurements in animals and humans.
3
Mori, Kensaku, Yuji K. Takahashi, Kei M. Igarashi, and Masahiro Yamaguchi. "Maps of Odorant Molecular Features in the Mammalian Olfactory Bulb." Physiological Reviews 86, no. 2 (April 2006): 409–33. http://dx.doi.org/10.1152/physrev.00021.2005.
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The olfactory bulb (OB) is the first relay station of the central olfactory system in the mammalian brain and contains a few thousand glomeruli on its surface. Because individual glomeruli represent a single odorant receptor, the glomerular sheet of the OB forms odorant receptor maps. This review summarizes the emerging view of the spatial organization of the odorant receptor maps. Recent studies suggest that individual odorant receptors are molecular-feature detecting units, and so are individual glomeruli in the OB. How are the molecular-feature detecting units spatially arranged in the glomerular sheet? To characterize the molecular-feature specificity of an individual glomerulus, it is necessary to determine the molecular receptive range (MRR) of the glomerulus and to compare the molecular structure of odorants within the MRR. Studies of the MRR mapping show that 1) individual glomeruli typically respond to a range of odorants that share a specific combination of molecular features, 2) each glomerulus appears to be unique in its MRR property, and 3) glomeruli with similar MRR properties gather together in proximity and form molecular-feature clusters. The molecular-feature clusters are located at stereotypical positions in the OB and might be part of the neural representation of basic odor quality. Detailed studies suggest that the glomerular sheet represents the characteristic molecular features in a systematic, gradual, and multidimensional fashion. The molecular-feature maps provide a basis for understanding how the olfactory cortex reads the odor maps of the OB.
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Pinnick, R. V., and V. J. Savin. "Filtration by superficial and deep glomeruli of normovolemic and volume-depleted rats." American Journal of Physiology-Renal Physiology 250, no. 1 (January 1, 1986): F86—F91. http://dx.doi.org/10.1152/ajprenal.1986.250.1.f86.
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We measured glomerular ultrafiltration coefficient (Kf) of isolated superficial (S) and deep (D) glomeruli of normovolemic and volume-depleted rats. Filtration was induced in vitro, and Kf was calculated from the maximum rate of change in glomerular size. Basement membrane area (A) for each glomerulus was estimated from morphometric analyses, and glomerular capillary hydraulic conductivity (Lp) was calculated by the formula Lp = Kf/A. Kf of S and D glomeruli of normovolemic rats were 2.98 +/- 0.98 and 4.25 +/- 0.07 nl . min-1 . mmHg-1, respectively. In hypovolemic rats, Kf of S glomeruli fell by approximately 50% to 1.52 +/- 0.14 nl . min-1 . mmHg-1 (P less than 0.001), whereas Kf of D glomeruli remained unchanged at 4.28 +/- 0.10 nl . min-1 . mmHg-1. Lp, calculated using the peripheral capillary area, averaged 1.98 +/- 0.09 and 1.98 +/- 0.06 microliter . min-1 . mmHg-1 . cm-2 in S and D glomeruli of normovolemic rats and 1.89 +/- 0.11 microliter . min-1 . mmHg-1 . cm-2 in D glomeruli of hypovolemic rats. Lp of S glomeruli of volume-depleted rats (0.90 +/- 0.03 microliter . min-1 . mmHg-1 . cm-2) was lower than in any of the other three samples. Mild hypovolemia causes the Kf of S glomeruli to decline, whereas Kf of D glomeruli remains constant. The decrease in Kf occurs without an alteration in capillary area and is most likely due to a decrease in Lp.
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Xie, Luke, Georgios Koukos, Kai Barck, Oded Foreman, Wyne P. Lee, Robert Brendza, Jeff Eastham-Anderson, Brent S. McKenzie, Andrew Peterson, and Richard A. D. Carano. "Micro-CT imaging and structural analysis of glomeruli in a model of Adriamycin-induced nephropathy." American Journal of Physiology-Renal Physiology 316, no. 1 (January 1, 2019): F76—F89. http://dx.doi.org/10.1152/ajprenal.00331.2018.
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Glomeruli number and size are important for determining the pathogenesis of glomerular disease, chronic kidney disease, and hypertension. Moreover, renal injury can occur in specific cortical layers and alter glomerular spatial distribution. In this study, we present a comprehensive structural analysis of glomeruli in a model of Adriamycin (doxorubicin) nephropathy. Glomeruli are imaged (micro-CT at 10 × 10 × 10 μm3) in kidney specimens from C57Bl/6 mouse cohorts: control treated with saline ( n = 9) and Adriamycin treated with 20 mg/kg Adriamycin ( n = 7). Several indices were examined, including glomerular number, glomerular volume, glomerular volume heterogeneity, and spatial density at each glomerulus and in each cortical layer (superficial, midcortical, and juxtamedullary). In the Adriamycin-treated animals, glomerular number decreased significantly in the left kidney [control: 8,298 ± 221, Adriamycin: 6,781 ± 630 (mean ± SE)] and right kidney (control: 7,317 ± 367, Adriamycin: 5,522 ± 508), and glomerular volume heterogeneity increased significantly in the left kidney (control: 0.642 ± 0.015, Adriamycin: 0.786 ± 0.018) and right kidney (control: 0.739 ± 0.016, Adriamycin: 0.937 ± 0.023). Glomerular spatial density was not affected. Glomerular volume heterogeneity increased significantly in the superficial and midcortical layers of the Adriamycin cohort. Adriamycin did not affect glomerular volume or density metrics in the juxtamedullary region, suggesting a compensatory mechanism of juxtamedullary glomeruli to injury in the outer cortical layers. Left/right asymmetry was observed in kidney size and various glomeruli metrics. The methods presented here can be used to evaluate renal disease models with subtle changes in glomerular endowment locally or across the entire kidney, and they provide an imaging tool to investigate diverse interventions and therapeutic drugs.
6
Makker, S. P. "Analysis of glomeruli-eluted Gp330 autoantibodies and of Gp330 antigen of Heymann nephritis." Journal of Immunology 151, no. 11 (December 1, 1993): 6500–6508. http://dx.doi.org/10.4049/jimmunol.151.11.6500.
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Abstract Quantity, charge, IgG isotype, Ag reactivity of glomerular gp330 autoantibodies (gp330Ab), and the charge of the putative Ag, gp330, were studied in active Heymann nephritis. Gp330 was anionic with an isoelectric point of 4.6. Despite variation in C3 glomerular immunofluorescence staining, C5b-9 staining was seen in all rats. Positive correlation was seen between glomerular gp330Ab and abnormal 24-h proteinuria (r = 0.637, p = 0.008), which appeared to require a certain threshold level of gp330Ab. Positive correlation was also seen between serum and glomerular gp330Ab at time of death (r = 0.55, p < 0.05). No differences were seen in charge, IgG isotypes of glomerular gp330Ab, or reactivity to gp330 by Western analysis in rats with or without abnormal proteinuria. Comparison of gp330Ab IgG isotypes in immune sera and glomeruli showed no difference in IgG1 and IgG2a, but IgG2b was significantly lower in glomeruli (p < 0.0001). Conclusions: 1) this is the first documentation that gp330 is highly anionic; 2) regardless of the degree of proteinuria, all immunized rats deposit in their glomeruli a qualitatively similar type of gp330Ab (charge, IgG isotype, complement activation, gp330 reactivity); 3) despite the highly anionic nature of gp330, anionic gp330Ab accumulate in glomeruli; and 4) complement activation appears to occur in every rat with gp330Ab in glomerulus and development of proteinuria is dependent on a certain threshold level of gp330Ab in the glomerulus which, in turn, correlates with the serum level of gp330Ab.
7
Hann, Bradley D., Edwin J. Baldelomar, Jennifer R. Charlton, and Kevin M. Bennett. "Measuring the intrarenal distribution of glomerular volumes from histological sections." American Journal of Physiology-Renal Physiology 310, no. 11 (June 1, 2016): F1328—F1336. http://dx.doi.org/10.1152/ajprenal.00382.2015.
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Glomerular volume is an important metric reflecting glomerular filtration surface area within the kidney. Glomerular hypertrophy, or increased glomerular volume, may be an important marker for renal stress. Current stereological techniques report the average glomerular volume (AVglom) within the kidney. These techniques cannot assess the spatial or regional heterogeneity common in developing renal pathology. Here, we report a novel “unfolding” technique to measure the actual distribution of individual glomerular volumes in a kidney from the two-dimensional glomerulus profiles observed by optical microscopy. The unfolding technique was first developed and tested for accuracy with simulations and then applied to measure the number of glomeruli ( Nglom), AVglom, and intrarenal distribution of individual glomerular volume (IVglom) in the oligosyndactyl (Os/+) mouse model compared with wild-type (WT) controls. The Os/+ mice had fewer and larger glomeruli than WT mice: Nglom was 12,126 ± 1,658 (glomeruli/kidney) in the WT mice and 5,516 ± 899 in the Os/+ mice; AVglom was 2.01 ± 0.28 × 10−4 mm3 for the WT mice and 3.47 ± 0.35 × 10−4 mm3 for the Os/+ mice. Comparing the glomerular volume distributions in Os/+ and WT kidneys, we observed that the Os/+ distribution peaked at a higher value of IVglom than the WT distribution peak, and glomeruli with a radius greater than 55 μm were more prevalent in the Os/+ mice (3.4 ± 1.6% of total glomeruli vs. 0.6 ± 1.2% in WT). Finally, the largest profiles were more commonly found in the juxtamedullary region. Unfolding is a novel stereological technique that provides a new quantitative view of glomerular volume distribution in the individual kidney.
8
Kitamura, Masanori. "TGF-β1 as an Endogenous Defender Against Macrophage-Triggered Stromelysin Gene Expression in the Glomerulus." Journal of Immunology 160, no. 10 (May 15, 1998): 5163–68. http://dx.doi.org/10.4049/jimmunol.160.10.5163.
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Abstract Recent investigation has indicated that TGF-β1, the macrophage (Mφ) deactivator, may attenuate Mφ-mediated acute glomerular injury. Using stromelysin as an indicator, this study investigated whether and how endogenous TGF-β1 modulates the glomerular cell activation triggered by Mφ. Rat mesangial cells were stably transfected with a cDNA encoding the active form of TGF-β1 and a cDNA coding for a dominant-negative mutant of the TGF-βR type II. Compared with mock-transfected cells, TGF-β1 transfectants exhibited blunted expression of stromelysin in response to the Mφ-derived, inflammatory cytokine IL-1β. In contrast, mesangial cells expressing the dominant-interfering TGF-βR showed enhanced expression of stromelysin in response to IL-1β, suggesting that endogenous TGF-β functions as an autocrine inhibitor of the IL-1 response. In isolated, normal rat glomeruli, externally added TGF-β1 suppressed the induction of stromelysin by mediators that were elaborated by activated Mφ. Similarly, when isolated, nephritic glomeruli producing the active form of TGF-β1 were stimulated by IL-1β or Mφ-conditioned medium, the induction of stromelysin was dramatically suppressed as compared with normal glomeruli. To investigate whether endogenous TGF-β1 affects the glomerular cell activation triggered by Mφ, a technique for adoptive Mφ transfer was used. LPS-stimulated reporter Mφ were transferred into either normal rat glomeruli or nephritic glomeruli expressing active TGF-β1. In the normal glomeruli, stromelysin expression was markedly induced in resident cells after the transfer of activated Mφ. This induction was substantially repressed in those glomeruli producing active TGF-β1. These results reinforce the idea that TGF-β1 is an endogenous defender that attenuates certain actions of infiltrating Mφ in the glomerulus.
9
Cortes, P., X. Zhao, B. L. Riser, and R. G. Narins. "Regulation of glomerular volume in normal and partially nephrectomized rats." American Journal of Physiology-Renal Physiology 270, no. 2 (February 1, 1996): F356—F370. http://dx.doi.org/10.1152/ajprenal.1996.270.2.f356.
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Glomerular extracellular matrix accumulation may derive from the stretching of mesangial cells caused by excessive glomerular dilatation. The relationship of glomerular volume (VG) to intraglomerular pressure, expressed as compliance or as mean VG in the isolated, perfused rat glomerulus, was used to analyze factors that regulate VG. Glomeruli were highly distensible over the normal and relevant abnormal range of pressure. Compliance increased directly with basal VG (P < 0.001), i.e., larger glomeruli dilated more than smaller ones at any given pressure. Perfusion with atrial natriuretic peptide did not alter compliance, and inhibitors of nitric oxide synthesis exerted only a trivial effect. VG expansion was consistently reduced by angiotensin II, but this effect was small (3.8%, P < 0.001). After subtotal nephrectomy, compliance increased by 59% in the remnant glomeruli (P < 0.001); 22% of this increase was attributable to structural changes, and the remainder was attributable to the large basal VG of the hypertrophied glomeruli. Thus the major determinants of VG expansion include capillary wall tension, basal VG, and intrinsic distensibility, which is markedly influenced by the character of the extracellular matrix and only slightly altered by an angiotensin II-modified mesangial cell tone.
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KITAMURA, MASANORI. "Renal Transfer of Genetically Engineered Cells." Journal of the American Society of Nephrology 11, suppl 2 (November 2000): S154—S158. http://dx.doi.org/10.1681/asn.v11suppl_2s154.
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Abstract. For many years, ex vivo gene transfer has been used for genetic manipulation of various organs. In the kidney, ex vivo gene transfer was reported using mesangial cells and macrophages. In rats, cultured cells injected into the renal artery are accumulated selectively in the glomerulus. With this approach, it is possible to transfer genetically engineered cells to normal and diseased glomeruli. The transfer of genetically engineered cells to glomeruli can be used for several purposes. With the use of resident glomerular cells engineered in vitro, it is possible to examine how the cells that overexpress certain genes behave differently in normal and diseased glomeruli. Both gain-of-function and loss-of-function strategies are useful for this purpose. For the latter, stable expression of antisense cDNA, ribosomes, or dominant-negative mutants is available. By transfer of engineered cells producing secretory, recombinant proteins, it is possible to modify glomerular microenvironment in vivo. Transfer of genes encoding therapeutically relevant molecules could be useful for therapeutic intervention. Transfer of engineered leukocytes to the glomerulus also allows investigation of cross talk between leukocytes and resident cells. Transfer of stimulated leukocytes is useful for investigation of the pathologic actions of infiltrating cells on glomerular structure and function. Leukocytes in which certain gene functions are selectively reinforced or deleted would be useful for elucidation of the exact functions of leukocyte-associated genes in glomerular diseases. This article summarizes current experience with the adoptive transfer of engineered cells to the glomerulus for investigation of and therapy for glomerular diseases.
11
Cortes, P., X. Zhao, F. Dumler, B. C. Tilley, and J. Atherton. "Age-related changes in glomerular volume and hydroxyproline content in rat and human." Journal of the American Society of Nephrology 2, no. 12 (June 1992): 1716–25. http://dx.doi.org/10.1681/asn.v2121716.
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Total 4-hydroxyproline content and volume were measured in the same sample of microdissected glomeruli obtained fro rat and human outer or inner cortex. Glomerular volume was determined by computer-assisted image analysis, and 4-hydroxyproline was measured by a highly sensitive gas-liquid chromatographic method. Results were expressed as weight of basement membrane material by comparison with the amount of 4-hydroxyproline in purified basement membrane/mesangial matrix preparations. Microanalyses were possible in samples containing as few as eight human glomeruli. Rat glomerular size increased sevenfold between 5 wk and 2 yr of age, with volume being consistently 36 to 45% greater in inner than in outer cortex glomeruli. Basement membrane material content per glomerulus markedly increased with age (12-fold); however, when expressed per unit volume, this change was greatly reduced (2-fold). Expressed per volume, inner and outer cortex glomerular content of basement membrane material was always similar, regardless of age. Therefore, a greater glomerular size, in itself, does not accelerate the rate of basement membrane material deposition. Glomerular size distributions (measured by skewness and kurtosis) did not change, indicating that, although glomerular volume increases with age, aging does not appear to cause the emergence of distinct glomerular populations within an age group. Basement membrane material accumulation is probably a generalized change. Human glomeruli increased sevenfold in size from infancy to adulthood and then declined during senescence. Contrary to that in the rat, glomerular basement membrane material content appeared to closely follow size changes, thus, varying little from infancy to senescence if expressed per unit of glomerular volume.
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Satoskar, Anjali A., Edward Calomeni, Cherri Bott, Gyongyi M. Nadasdy, and Tibor Nadasdy. "Focal Glomerular Immune Complex Deposition: Possible Role of Periglomerular Fibrosis/Atubular Glomeruli." Archives of Pathology & Laboratory Medicine 133, no. 2 (February 1, 2009): 283–88. http://dx.doi.org/10.5858/133.2.283.
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Abstract Context.—Consensus exists among renal pathologists that, in biopsies with immune complex glomerulonephritis, even a single glomerulus with open capillary loops may be sufficient for immunofluorescence and/or electron microscopy evaluation because immune complex deposition is a diffuse phenomenon. However, we have encountered renal biopsies with focal absence of immune complexes in glomeruli on either immunofluorescence or electron microscopy examination despite presence of open glomerular capillary loops. Objective.—To evaluate renal biopsies with focal immune complex deposition and look for any subtle or unusual morphologic changes in the glomeruli (and in the biopsy in general). Design.—Native and transplant renal biopsies were reviewed. All biopsies had been triaged and processed according to our routine protocol for light microscopy, immunofluorescence, and electron microscopy examination. Results.—Of 2018 renal biopsies from December 2005 to December 2007, we found 10 such biopsies; 5 native and 5 transplant kidney biopsies. We found that the glomeruli with absent immune complex deposits had periglomerular fibrosis with open, albeit, wrinkled appearing capillary loops but no glomerular sclerosis. Conclusions.—We hypothesize that these histologic features are indicative of nonfunctional glomeruli and may be associated with disconnection between the Bowman capsule and proximal tubule (atubular glomeruli). These glomeruli may not have effective filtration, despite some degree of circulation through the open capillary loops, and therefore are unable to accumulate immune complex deposits. If biopsies are small and only such glomeruli are available for immunofluorescence or electron microscopy examination, the absence of immune complex deposition in them should be evaluated carefully.
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Tank, J. E., O. W. Moe, R. A. Star, and W. L. Henrich. "Differential regulation of rat glomerular and proximal tubular renin mRNA following uninephrectomy." American Journal of Physiology-Renal Physiology 270, no. 5 (May 1, 1996): F776—F783. http://dx.doi.org/10.1152/ajprenal.1996.270.5.f776.
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Angiotensin II is thought to play a role in the renal adaptations to reduced renal mass, but earlier work has shown that plasma renin activity (PRA) does not increase in this setting. To examine this paradox, we studied the effect of uninephrectomy (UNX) on circulating, juxtaglomerular, glomerular, and proximal tubular (PT) renin. PRA was unchanged 2 wk following UNX and fell slightly at 6 wk. Single kidney renin secretory capacity and cortical renin mRNA, reflecting juxtaglomerular renin, were unchanged at 2 and 6 wk. With quantitative competitive reverse transcription-polymerase chain reaction, renin mRNA in microdissected glomeruli and PT were dramatically increased 2 wk post-UNIX (for glomeruli: sham, 1.2 +/- 0.3, vs. UNX, 8.8 +/- 1.9 x 10(5) copies/glomerulus; for PT: sham, 4.6 +/- 0.9, vs. UNX, 17.7 +/- 5.1 x 10(3) copies/mm). By 6 wk, glomerular renin was unchanged, and PT renin mRNA was markedly suppressed (for glomeruli; sham, 2.9 +/- 1.2, vs. UNX, 4.2 +/- 1.1 x 10(5) copies/glomerulus; for PT: sham, 7.5 +/- 2.1, vs. UNX, 1.0 +/- 0.3 x 10(3) copies/mm). These results demonstrate differential regulation of the circulating, juxtaglomerular, glomerular, and PT renin systems. Early activation of glomerular and PT renin may result in increased local generation of angiotensin II and thereby affect renal structural and functional adaptations following UNX.
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Atiyeh, B. A., B. S. Arant, W. L. Henrich, and M. G. Seikaly. "In vitro production of angiotensin II by isolated glomeruli." American Journal of Physiology-Renal Physiology 268, no. 2 (February 1, 1995): F266—F272. http://dx.doi.org/10.1152/ajprenal.1995.268.2.f266.
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The glomerulus has several components of the renin-angiotensin system (RAS). The purpose of this study was to evaluate the ability of glomeruli isolated from adult Wistar-Kyoto rats to produce angiotensin II (ANG II). When isolated glomeruli were incubated in Krebs buffer, the peak concentration of immunoreactive angiotensin (ANG) in the incubation medium, representing simultaneous production and degradation, occurred after 15 min of incubation (3.98 +/- 0.34 pg.mg protein-1.15 min-1, of which 18% was ANG II. When 125I-labeled ANG II was incubated with isolated glomeruli, the half-life of ANG II was 6.06 min. Hence, we estimated ANG II production at 3.77 +/- 0.21 pg.mg protein-1.15 min-1. When angiotensinogen-rich serum was added to the incubation medium, ANG concentration at 15 min increased by 500-fold (1,978 +/- 44 pg.mg protein-1.15 min-1, P < 0.001). ANG concentration in the glomerular incubate responded to perturbations known to alter systemic RAS. Enalaprilat, chymostatin, propranolol, and renin antiserum decreased ANG concentration in glomerular incubate, whereas salt depletion increased this (P < 0.05). We conclude that the rat glomerulus can generate ANG II independent of neural, hormonal, or vascular control.
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Gupta, A., B. Bastani, H. Purcell, and K. A. Hruska. "Identification and localization of pertussis toxin-sensitive GTP-binding proteins in bovine kidney glomeruli." Journal of the American Society of Nephrology 2, no. 2 (August 1991): 172–78. http://dx.doi.org/10.1681/asn.v22172.
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The vascular tree and the mesangium in the glomerulus respond to various hormones, growth factors, and autonomic signals, leading to generation of second messengers and regulation of ion channels. Guanine nucleotide regulatory proteins (G proteins) mediate these effects in other systems. Glomerular G proteins were studied by immunoblotting and immunohistochemical techniques. Glomeruli were isolated from bovine kidney cortex by differential sieving. Glomerular proteins were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and nitrocellulose transfers were immunoblotted with antibodies to G proteins. G alpha,common antiserum (P-960) recognized proteins with a molecular mass of 41 to 45 kDa. Antibodies against peptide sequences specific to Gi alpha and Go alpha demonstrated Gi alpha, 1/3 (molecular mass, 39 to 41 kDa), Gi alpha 2 (molecular mass, 40 kDa), and Go alpha (molecular mass, 39 kDa). Presence of these proteins was further confirmed by pertussis toxin-catalyzed ADP ribosylation of protein(s) with a molecular mass of 39 to 41 kDa in the glomeruli. Immunohistochemical staining of frozen sections from bovine kidney cortex revealed the presence of Gi alpha 2 in capillary loop distribution in glomeruli and interstitium, but Gi,1/3 or Go could not be demonstrated. The pattern of immunofluorescence with Gi alpha 2 antiserum suggested localization of Gi alpha 2 to the endothelium in glomerular and interstitial vasculature. The novel finding of Go in glomeruli requires localization of Go to specific cells and determination of its role in glomerular physiology. In conclusion, these studies demonstrate that bovine kidney glomeruli express alpha subunits of pertussis toxin-sensitive GTP-binding proteins Gi,1/3, Gi,2 and Go.(ABSTRACT TRUNCATED AT 250 WORDS)
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Roeder, Sebastian S., Ania Stefanska, Diana G. Eng, Natalya Kaverina, Maria W. Sunseri, Bairbre A. McNicholas, Peter Rabinovitch, et al. "Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age." American Journal of Physiology-Renal Physiology 309, no. 2 (July 15, 2015): F164—F178. http://dx.doi.org/10.1152/ajprenal.00144.2015.
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Kidney aging is accompanied by characteristic changes in the glomerulus, but little is known about the effect of aging on glomerular parietal epithelial cells (PECs), nor if the characteristic glomerular changes in humans and rats also occur in very old mice. Accordingly, a descriptive analysis was undertaken in 27-mo-old C57B6 mice, considered advanced age. PEC density was significantly lower in older mice compared with young mice (aged 3 mo), and the decrease was more pronounced in juxtamedullary glomeruli compared with outer cortical glomeruli. In addition to segmental and global glomerulosclerosis in older mice, staining for matrix proteins collagen type IV and heparan sulfate proteoglycan were markedly increased in Bowman's capsules of older mouse glomeruli, consistent with increased extracellular matrix production by PECs. De novo staining for CD44, a marker of activated and profibrotic PECs, was significantly increased in aged glomeruli. CD44 staining was more pronounced in the juxtamedullary region and colocalized with phosphorylated ERK. Additionally, a subset of aged PECs de novo expressed the epithelial-to-mesenchymal transition markers α-smooth muscle and vimentin, with no changes in epithelial-to-mesenchymal transition markers E-cadherin and β-catenin. The mural cell markers neural/glial antigen 2, PDGF receptor-β, and CD146 as well as Notch 3 were also substantially increased in aged PECs. These data show that mice can be used to better understand the aging kidney and that PECs undergo substantial changes, especially in juxtamedullary glomeruli, that may participate in the overall decline in glomerular structure and function with advancing age.
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Riegel, JA. "Analysis of fluid dynamics in perfused glomeruli of the hagfish eptatretus stouti (Lockington)." Journal of Experimental Biology 201, no. 22 (November 1, 1998): 3097–104. http://dx.doi.org/10.1242/jeb.201.22.3097.
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The capillary tuft of glomeruli of the hagfish mesonephros contains both 'low'-pressure and 'high'-pressure glomerular vessels (LPGVs and HPGVs). The existence of the HPGV raised the possibility that pressure filtration could occur in the hagfish kidney when the blood pressure was sufficiently high. Therefore, measurements of glomerular capillary pressure were made in HPGVs and LPGVs whilst single glomeruli were perfused with hagfish Ringer's solution that contained the colloid Ficoll 70. Calculations of the effective colloid osmotic pressure in perfused capillaries were made; these showed that hydrostatic pressures within the HPGV were inadequate to effect pressure filtration except at high rates of perfusion. However, high rates of perfusion provoked perfusion pressures that exceeded the highest values measured in the renal blood supply of lightly anaesthetised hagfish. It was concluded that some process other than pressure filtration must account for formation of the primary urine by hagfish glomeruli. The proportion of the perfusate that became urine, the single glomerulus filtration fraction (SGFF), bore a strong positive relationship to the vascular resistance of perfused glomeruli. Both the SGFF and the vascular resistance were inversely related to the rate of perfusion except when that rate was very high. From these two observations it was concluded that at least two flow pathways exist in hagfish glomeruli: one that has a high vascular resistance and that contributes to the elaboration of the urine, and one that has a low vascular resistance and does not contribute to urine formation. The possible anatomical location of the various flow pathways through hagfish glomeruli and how they may function are discussed.
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Shankland, S. J., P. Hamel, and J. W. Scholey. "Cyclin and cyclin-dependent kinase expression in the remnant glomerulus." Journal of the American Society of Nephrology 8, no. 3 (March 1997): 368–75. http://dx.doi.org/10.1681/asn.v83368.
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Recent studies suggest that subtotal renal ablation is associated with an early phase of mesangial cell proliferation. Because the mechanism(s) responsible for this response have not been elucidated, the study presented here sought to determine if changes in expression of positive cell cycle regulators, including pRb, cyclin E, and cdk2, occurred in the glomerulus during the early period of compensatory renal hypertrophy that follows 5/6 renal ablation. A first group of rats underwent sham operation and served as the control group. A second group of rats underwent 5/6 renal ablation. Ninety-six hours after subtotal ablation, protein was extracted from sieved glomeruli for Western blot analysis of proliferating cell nuclear antigen (PCNA) and retinoblastoma protein expression (pRb). RNA was extracted from sieved glomeruli for Northern blot analysis of cyclin E and cdk2 mRNA levels, and renal cortical tissue was subjected to immunohistochemical analysis of PCNA. On average, one PCNA-positive nucleus was present every 22 glomerular profiles in normal rats. The number of PCNA-positive nuclei increased fivefold in glomeruli, 96 h after renal ablation (P < 0.05). pRb was present only in the unphosphorylated state in normal glomeruli, but the increase in PCNA was accompanied by the appearance of phosphorylated pRb in remnant glomeruli. mRNA levels for cyclin E increased twofold in remnant glomeruli, whereas mRNA levels for cdk2 were unchanged. It was concluded that renal ablation leads to cell cycle progression in the glomerulus and an increase in the G1 cyclin, cyclin E, is associated with the appearance of phosphorylated retinoblastoma protein.
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Sütö, T. S., L. G. Fine, F. Shimizu, and M. Kitamura. "In vivo transfer of engineered macrophages into the glomerulus: endogenous TGF-beta-mediated defense against macrophage-induced glomerular cell activation." Journal of Immunology 159, no. 5 (September 1, 1997): 2476–83. http://dx.doi.org/10.4049/jimmunol.159.5.2476.
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Abstract Communication between resident glomerular cells and infiltrating macrophages plays a crucial role in the pathogenesis of glomerular disease. Using matrix metalloproteinase-9 (MMP-9) as an indicator molecule, we examined the interaction between mesangial cells and macrophages. Mesangial cells cocultured with activated macrophages or exposed to macrophage-conditioned media produced abundant MMP-9. We identified the stimulator secreted by macrophages as IL-1 because mesangial cells overexpressing IL-1 receptor antagonist protein showed a blunted expression of MMP-9 in response to the macrophage-conditioned medium. In contrast, culture supernatants of mesangial cells inhibited MMP-9 production by macrophages in a dose-dependent fashion. This inhibitor was identified to be TGF-beta1, since neutralization of TGF-beta1 abrogated the inhibitory effect of the mesangial cell-conditioned medium. To investigate whether activated macrophages induce glomerular MMP-9 expression, and if so, how endogenous TGF-beta1 modulates the induction, stimulated reporter macrophages were transferred into normal rat glomeruli or glomeruli in the regeneration phase of acute anti-Thy-1 glomerulonephritis. In the normal glomeruli, MMP-9 expression was up-regulated in resident cells after the transfer of activated macrophages. This induction was substantially repressed in the regenerating glomeruli that produced active TGF-beta1. These results point to potential mechanisms involved in glomerular control of MMP-9. Based upon the in vitro evidence, TGF-beta1 was identified as an endogenous "defender" that attenuates certain actions of infiltrating macrophages in the glomerulus.
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Zak, Joseph D., Jennifer D. Whitesell, and Nathan E. Schoppa. "Metabotropic glutamate receptors promote disinhibition of olfactory bulb glomeruli that scales with input strength." Journal of Neurophysiology 113, no. 6 (March 15, 2015): 1907–20. http://dx.doi.org/10.1152/jn.00222.2014.
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Increasing evidence indicates that the neural circuitry within glomeruli of the olfactory bulb plays a major role in affecting information flow between olfactory sensory neurons (OSNs) and output mitral cells (MCs). Glutamatergic external tufted (ET) cells, located at glomeruli, can act as intermediary cells in excitation between OSNs and MCs, whereas activation of MCs by OSNs is, in turn, suppressed by inhibitory synapses onto ET cells. In this study, we used patch-clamp recordings in rat olfactory bulb slices to examine the function of metabotropic glutamate receptors (mGluRs) in altering these glomerular signaling mechanisms. We found that activation of group II mGluRs profoundly reduced inhibition onto ET cells evoked by OSN stimulation. The mGluRs that mediated disinhibition were located on presynaptic GABAergic periglomerular cells and appeared to be activated by glutamate transients derived from dendrites in glomeruli. In terms of glomerular output, the mGluR-mediated reduction in GABA release led to a robust increase in the number of action potentials evoked by OSN stimulation in both ET cells and MCs. Importantly, however, the enhanced excitation was specific to when a glomerulus was strongly activated by OSN inputs. By being selective for strong vs. weak glomerular activation, mGluR-mediated disinhibition provides a mechanism to enhance the contrast in odor signals that activate OSN inputs into a single glomerulus at varying intensities.
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Ogura, A., H. Fujimura, T. Asano, M. Koura, I. Naito, and Y. Kobayashi. "Early Ultrastructural Glomerular Alterations in Neonatal Nephrotic Mice (ICGN Strain)." Veterinary Pathology 32, no. 3 (May 1995): 321–23. http://dx.doi.org/10.1177/030098589503200317.
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ICGN is a strain of mice with hereditary nephrotic syndrome of an unknown cause. In this study, early glomerular alterations in newborn ICGN mice were observed with electron microscopy to gain a better insight into the onset of the disease. Development of the glomeruli was normal until fusion of epithelial and endothelial basement membranes in the developing capillary stage. From the maturing glomerulus stage onward, the fused glomerular basement membrane (GBM) increased in thickness by excessive accumulation of the basement membrane material secreted from the epithelial cells. This accumulation was followed by overall loss of epithelial foot processes in the glomeruli. These findings indicate that the disease in ICGN mice is caused by some defect(s) in the GBM maturation process, which may be crucial for the generation of the glomerular permselectivity.
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Ito, Takahito, Akira Suzuki, Enyu Imai, Masaru Okabe, and Masatsugu Hori. "Bone Marrow Is a Reservoir of Repopulating Mesangial Cells during Glomerular Remodeling." Journal of the American Society of Nephrology 12, no. 12 (December 2001): 2625–35. http://dx.doi.org/10.1681/asn.v12122625.
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ABSTRACT. The renal glomerulus, whose cellular components are developmentally derived from the mesenchyme, plays a pivotal role in filtratating plasma. Irretrievable changes of glomerular components are responsible for the initiation and progression of impaired renal function. Recently, it has been shown that functional stem cells exist in the bone marrow of adult bodies and that they can reconstitute damaged tissues of the mesenchymal origin. To examine whether the bone marrow provides stem cells to damaged glomeruli, transgenic rats carrying enhanced green fluorescence protein (EGFP rat) were established in a systemic and constitutive manner. After transplanting the bone marrow of EGFP rats into wild-type rats, the progeny of the transplanted marrow cells were tracked with a tag of EGFP. Recruitment of bone marrow-derived cells into glomeruli was dramatically facilitated in response to mesangiolysis evoked in anti-Thy1 antibody-mediated glomerulonephritis. In the restored glomeruli, 11% to 12% of glomerular cells were derived from the transplanted bone marrow. The number of bone marrow-derived CD45+ cells transiently increased during the disease process, and CD45-negative cells constantly accounted for more than half of the bone marrow-derived population in glomeruli. Bone marrow-derived Thy1+ cells kept increasing in number until the remodeling ceased and finally made up 7% to 8% of glomerular cells. Laser scanning microscopy displayed that the bone marrow-derived Thy1+ cells provide structural support for glomerular capillaries, which indicates that they are mesangial cells. Although CD45−Thy1− bone marrow-derived cells exist during the remodeling of glomeruli, none of them expressed endothelial markers such as Factor VIII and RECA1 as long as they were tested. The results indicate that the bone marrow can give rise to mesangial cells in vivo.
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Carome, M. A., L. J. Striker, E. P. Peten, S. J. Elliot, C. W. Yang, W. G. Stetler-Stevenson, P. Reponen, K. Tryggvason, and G. E. Striker. "Assessment of 72-kilodalton gelatinase and TIMP-1 gene expression in normal and sclerotic murine glomeruli." Journal of the American Society of Nephrology 5, no. 6 (December 1994): 1391–99. http://dx.doi.org/10.1681/asn.v561391.
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Mice transgenic for bovine growth hormone (bGH) develop progressive diffuse glomerulosclerosis. Because murine mesangial cells in vitro were found to express the genes for 72-kd gelatinase and the metalloproteinase inhibitor TIMP-1, the expression of these genes in vivo in isolated whole glomeruli from bGH mice and normal control littermates was examined. Intact glomeruli were isolated by microdissection and subjected to reverse transcription. TIMP-1 cDNA was not detected by standard polymerase chain reaction (PCR) in glomeruli from bGH or control mice. In contrast, cDNA for 72-kd gelatinase was detected by standard PCR in both bGH and control mice, and the level was subsequently measured by quantitative competitive PCR. The gelatinase cDNA level was 14.7 +/- 2.8 x 10(-4) attomoles/glomerulus in 2- to 3-month-old control mice and was unchanged in 6-month-old controls. The bGH mice had 3.5-fold and 4.5-fold higher cDNA levels at 2 to 3 months and 6 months of age, respectively. Finally, zymography of glomerular extracts revealed increased levels of 72-kd and 96- to 100-kd gelatinase activity in bGH glomeruli in comparison to that in controls. In summary, whereas the genes for both TIMP-1 and 72-kd gelatinase are expressed in vitro in cultured mesangial cells, only the gelatinase gene appeared to be expressed in vivo in intact glomeruli. In addition, there was an up-regulation in the glomerular expression of the 72-kd gelatinase in bGH mice, a murine model of glomerulosclerosis.
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Wyss, Hans M., Joel M. Henderson, Fitzroy J. Byfield, Leslie A. Bruggeman, Yaxian Ding, Chunfa Huang, Jung Hee Suh, et al. "Biophysical properties of normal and diseased renal glomeruli." American Journal of Physiology-Cell Physiology 300, no. 3 (March 2011): C397—C405. http://dx.doi.org/10.1152/ajpcell.00438.2010.
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The mechanical properties of tissues and cells including renal glomeruli are important determinants of their differentiated state, function, and responses to injury but are not well characterized or understood. Understanding glomerular mechanics is important for understanding renal diseases attributable to abnormal expression or assembly of structural proteins and abnormal hemodynamics. We use atomic force microscopy (AFM) and a new technique, capillary micromechanics, to measure the elastic properties of rat glomeruli. The Young's modulus of glomeruli was 2,500 Pa, and it was reduced to 1,100 Pa by cytochalasin and latunculin, and to 1,400 Pa by blebbistatin. Cytochalasin or latrunculin reduced the F/G actin ratios of glomeruli but did not disrupt their architecture. To assess glomerular biomechanics in disease, we measured the Young's moduli of glomeruli from two mouse models of primary glomerular disease, Col4a3−/− mice (Alport model) and Tg26HIV/nl mice (HIV-associated nephropathy model), at stages where glomerular injury was minimal by histopathology. Col4a3−/− mice express abnormal glomerular basement membrane proteins, and Tg26HIV/nl mouse podocytes have multiple abnormalities in morphology, adhesion, and cytoskeletal structure. In both models, the Young's modulus of the glomeruli was reduced by 30%. We find that glomeruli have specific and quantifiable biomechanical properties that are dependent on the state of the actin cytoskeleton and nonmuscle myosins. These properties may be altered early in disease and represent an important early component of disease. This increased deformability of glomeruli could directly contribute to disease by permitting increased distension with hemodynamic force or represent a mechanically inhospitable environment for glomerular cells.
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Messenger, E. A., C. Stonier, and G. M. Aber. "Differences in glomerular binding and response to angiotensin II between normotensive and spontaneously hypertensive rats." Clinical Science 75, no. 2 (August 1, 1988): 191–96. http://dx.doi.org/10.1042/cs0750191.
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1. Angiotensin II (ANG II) binding and the physiological response to exogenous ANG II have been studied in isolated glomerular preparations from normotensive (NTR) and spontaneously hypertensive (SHR) rats. 2. The binding of 125I-labelled ANG II by glomeruli from SHR was significantly greater than that by glomeruli from NTR, whereas the binding affinity constant (Ka) showed that the SHR ANG II glomerular receptor had a lower affinity for the hormone than the NTR glomerular receptor. 3. Glomeruli from SHR were significantly less responsive to exogenous ANG II than those from NTR. 4. Sodium loading resulted in a significant increase in ANG II binding by glomeruli from NTR, whereas a decrease in binding occurred in glomeruli from SHR. 5. Although a high sodium intake caused a reduction in the response of glomeruli from both NTR and SHR to exogenous ANG II, these changes were not statistically significant. In NTR this was associated with a decrease in the concentration of agonist required to cause half-maximal response (EC50), whereas an increase in EC50 was shown by glomeruli from SHR.
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Norling, L. L., C. A. Vaughan, and R. L. Chevalier. "Maturation of cGMP response to ANP by isolated glomeruli." American Journal of Physiology-Renal Physiology 262, no. 1 (January 1, 1992): F138—F143. http://dx.doi.org/10.1152/ajprenal.1992.262.1.f138.
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Experiments were done to determine whether there is a maturational increase in production of guanosine 3',5'-cyclic monophosphate (cGMP) by glomeruli or in eggression of cGMP out of glomerular cells. Both preweaned and adult isolated rat glomeruli responded with an acute rise in intracellular cGMP after 0.5-min exposure to 0.1 microM ANP. However, at 4 h extracellular cGMP was significantly greater in ANP-treated adult compared with preweaned glomeruli (P less than 0.005). In the absence of 3-isobutyl-1-methylxanthine (IBMX) intracellular cGMP was significantly higher in preweaned glomeruli (P less than 0.05). Moreover, the specific activity of phosphodiesterases for cGMP hydrolysis was twofold less in preweaned glomerular membranes (P less than 0.004). Finally, probenecid decreased export of adult glomerular cGMP by 60 +/- 4%, whereas preweaned glomerular cGMP export decreased by only 27 +/- 4% (P less than 0.05). In conclusion, compared with adult, ANP-treated preweaned glomeruli export less cGMP out of glomerular cells, have a higher concentration of intracellular cGMP, and have lower cGMP-specific phosphodiesterase activity, and the organic ion transporter in preweaned glomerular cells exports cGMP less effectively. The limited transport of cGMP out of preweaned glomeruli may account for the blunted natriuretic and diuretic response following ANP stimulation of young rats.
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Beavan, L. A., M. Davies, and R. M. Mason. "Renal glomerular proteoglycans. An investigation of their synthesis in vivo using a technique for fixation in situ." Biochemical Journal 251, no. 2 (April 15, 1988): 411–18. http://dx.doi.org/10.1042/bj2510411.
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Newly synthesized rat glomerular [35S]proteoglycans were labelled in vivo after injecting Na2[35S]SO4 intraperitoneally. At the end of the labelling period (7 h) the kidneys were perfused in situ with 0.01% (w/v) cetylpyridinium chloride. This fixed proteoglycans in the tissue and increased their recovery 2-3-fold during subsequent isolation of glomeruli from the renal cortex. The glomeruli were fractionated by a modified osmotic lysis and detergent extraction procedure [Meezan, Brendel, Hjelle & Carlson (1978) in The Biology and Chemistry of Basement Membranes (Kefalides, N.A., ed.), Academic Press, New York; Kanwar & Farquhar (1979) Proc. Natl. Acad. Sci. U.S.A. 76, 4493-4497] to obtain a basement membrane preparation. The proteoglycans released at each stage of the procedure were characterized using DEAE-Sephacel ion-exchange chromatography, chondroitinase ABC and HNO2 digestion and Sepharose CL-4B gel-permeation chromatography. About 85% of the [35S]proteoglycans synthesized were of the heparan sulphate variety, the remainder being chondroitin sulphate proteoglycans. Three sizes of heparan sulphate proteoglycans were identified. The largest (HS1, Kav. 0.47) accounts for 44% of the total extractable heparan sulphates. About one third of HS1 were extracted from the glomerular basement-membrane fraction with 8 M-urea and 4 M-guanidine hydrochloride but the remainder were released from the glomerulus during preparation of the fraction. The two smaller molecules (HS2, Kav. 0.56 and HS3, Kav. 0.68) accounted for 27% and 28% of the extractable heparan sulphate respectively and were not associated with the basement membrane fraction. HS1, HS2 and HS3 were also isolated from non-fixed glomeruli labelled in vivo but with much lower recovery. In glomeruli labelled in vitro, heparan sulphate accounted for only 35% of the proteoglycans, the remainder being of the chondroitin sulphate type. Proteoglycans similar to HS1, HS2 and HS3 were present in glomeruli labelled in vitro but, in addition, a large, highly charged heparan sulphate (HS1a) was extracted from the glomerular basement-membrane fraction of these glomeruli. It accounted for 6% of the total heparan sulphate.
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Fan, Fan, Chun Cheng Andy Chen, Jin Zhang, Carlos M. N. Schreck, Eric A. Roman, Jan M. Williams, Takashi Hirata, et al. "Fluorescence dilution technique for measurement of albumin reflection coefficient in isolated glomeruli." American Journal of Physiology-Renal Physiology 309, no. 12 (December 15, 2015): F1049—F1059. http://dx.doi.org/10.1152/ajprenal.00311.2015.
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This study describes a high-throughput fluorescence dilution technique to measure the albumin reflection coefficient (σAlb) of isolated glomeruli. Rats were injected with FITC-dextran 250 (75 mg/kg), and the glomeruli were isolated in a 6% BSA solution. Changes in the fluorescence of the glomerulus due to water influx in response to an imposed oncotic gradient was used to determine σAlb. Adjustment of the albumin concentration of the bath from 6 to 5, 4, 3, and 2% produced a 10, 25, 35, and 50% decrease in the fluorescence of the glomeruli. Pretreatment of glomeruli with protamine sulfate (2 mg/ml) or TGF-β1 (10 ng/ml) decreased σAlbfrom 1 to 0.54 and 0.48, respectively. Water and solute movement were modeled using Kedem-Katchalsky equations, and the measured responses closely fit the predicted behavior, indicating that loss of albumin by solvent drag or diffusion is negligible compared with the movement of water. We also found that σAlbwas reduced by 17% in fawn hooded hypertensive rats, 33% in hypertensive Dahl salt-sensitive (SS) rats, 26% in streptozotocin-treated diabetic Dahl SS rats, and 21% in 6-mo old type II diabetic nephropathy rats relative to control Sprague-Dawley rats. The changes in glomerular permeability to albumin were correlated with the degree of proteinuria in these strains. These findings indicate that the fluorescence dilution technique can be used to measure σAlbin populations of isolated glomeruli and provides a means to assess the development of glomerular injury in hypertensive and diabetic models.
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Beeman, Scott C., Luise A. Cullen-McEwen, Victor G. Puelles, Min Zhang, Teresa Wu, Edwin J. Baldelomar, John Dowling, et al. "MRI-based glomerular morphology and pathology in whole human kidneys." American Journal of Physiology-Renal Physiology 306, no. 11 (June 1, 2014): F1381—F1390. http://dx.doi.org/10.1152/ajprenal.00092.2014.
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Nephron number ( Nglom) and size (Vglom) are correlated with risk for chronic cardiovascular and kidney disease and may be predictive of renal allograft viability. Unfortunately, there are no techniques to assess Nglom and Vglom in intact kidneys. This work demonstrates the use of cationized ferritin (CF) as a magnetic resonance imaging (MRI) contrast agent to measure Nglom and Vglom in viable human kidneys donated to science. The kidneys were obtained from patients with varying levels of cardiovascular and renal disease. CF was intravenously injected into three viable human kidneys. A fourth control kidney was perfused with saline. After fixation, immunofluorescence and electron microscopy confirmed binding of CF to the glomerulus. The intact kidneys were imaged with three-dimensional MRI and CF-labeled glomeruli appeared as punctate spots. Custom software identified, counted, and measured the apparent volumes of CF-labeled glomeruli, with an ∼6% false positive rate. These measurements were comparable to stereological estimates. The MRI-based technique yielded a novel whole kidney distribution of glomerular volumes. Histopathology demonstrated that the distribution of CF-labeled glomeruli may be predictive of glomerular and vascular disease. Variations in CF distribution were quantified using image texture analyses, which be a useful marker of glomerular sclerosis. This is the first report of direct measurement of glomerular number and volume in intact human kidneys.
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Denic, Aleksandar, Jerry Mathew, Venkata V. Nagineni, R. Houston Thompson, Bradley C. Leibovich, Lilach O. Lerman, John C. Lieske, et al. "Clinical and Pathology Findings Associate Consistently with Larger Glomerular Volume." Journal of the American Society of Nephrology 29, no. 7 (May 22, 2018): 1960–69. http://dx.doi.org/10.1681/asn.2017121305.
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Background Glomerular volume increases when demand exceeds nephron supply, which may lead to glomerulosclerosis. It is unclear if determinants of glomerular volume are consistent between populations that differ by severity of comorbidities.Methods We studied kidney biopsy specimens from living kidney donors (n=2453) and patients who underwent radical nephrectomy for a renal tumor (n=780). We scanned specimen sections into high-resolution digital images, manually traced glomerular profiles, and calculated mean glomerular volumes using the Weibel–Gomez stereologic formula (separately for nonsclerosed glomeruli and globally sclerosed glomeruli). We then assessed the relationship of glomerular volume with age, clinical characteristics, and nephrosclerosis on biopsy specimen.Results Compared with kidney donors, patients with tumors were older and more frequently men, obese, diabetic, or hypertensive, had more glomerulosclerosis and interstitial fibrosis on biopsy specimen, and had 12% larger nonsclerosed glomeruli (P<0.001). In both populations, male sex, taller height, obesity, hypertension, and proteinuria associated with larger nonsclerosed glomeruli to a similar extent. In patients with tumors, diabetes, glomerulosclerosis >25%, and interstitial fibrosis >25% also associated with larger nonsclerosed glomeruli. Independent clinical predictors of larger nonsclerotic glomeruli were family history of ESRD, male sex, taller height, obesity, diabetes, and proteinuria. After adjustment for these characteristics, nonsclerotic glomerular volume did not differ between populations and was stable up to age 75 years, after which it decreased with age. Many of these findings were also evident with globally sclerotic glomerular volume.Conclusions Characteristics associated with glomerular volume are consistent between patient populations with low and high levels of comorbidity.
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Rovin, B. H., J. B. Lefkowith, and G. F. Schreiner. "Mechanisms underlying the anti-inflammatory effects of essential fatty acid deficiency in experimental glomerulonephritis. Inhibited release of a monocyte chemoattractant by glomeruli." Journal of Immunology 145, no. 4 (August 15, 1990): 1238–45. http://dx.doi.org/10.4049/jimmunol.145.4.1238.
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Abstract Injection of nephrotoxic serum into rats results in glomerular inflammation and proteinuria. Rats placed on an essential fatty acid (EFA)-deficient diet are protected from the glomerular macrophage infiltration and the ensuing proteinuria. To account for this protection, we studied EFA-deficient rats to determine if there were defects in macrophage chemotaxis. We also investigated the possibility that EFA deficiency diminishes the production of a glomerular chemoattractant for monocytes. In microchemotaxis assays EFA-deficient macrophages migrated normally. EFA-deficient serum did not appear to contain a chemotactic inhibitor. Cultured glomeruli from control and control nephritic rats were found to elaborate a chemoattractant for monocytes. This chemoattractant activity was markedly enhanced after induction of nephritis, was heat stable, was not altered by inhibition of cyclooxygenase, lipoxygenase, or platelet-activating factor, and did not depend on C or the glomerular inflammatory cell infiltrate. EFA-deficient glomeruli harvested from animals receiving injections with nephrotoxic serum produced markedly less chemoattractant activity than glomeruli from control nephritic animals. Lipid extraction of nephritic glomeruli from control animals yielded chemoattractant activity in the organic phase. Extracts of EFA-deficient nephritic glomeruli had considerably less activity. We propose that EFA deficiency attenuates glomerular inflammation by inhibiting the ability of glomeruli to produce a specific lipid monocyte chemoattractant after exposure to a nephritic stimulus.
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McDowell, K. A., R. L. Chevalier, B. A. Thornhill, and L. L. Norling. "Unilateral ureteral obstruction increases glomerular soluble guanylyl cyclase activity." Journal of the American Society of Nephrology 6, no. 5 (November 1995): 1498–503. http://dx.doi.org/10.1681/asn.v651498.
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RBF and GFR are decreased in kidneys after ipsilateral unilateral ureteral obstruction (UUO) for 24 h. Despite net vasoconstriction, vasodilatory mechanisms respond to counterbalance the vasoconstriction: the inhibition of nitric oxide synthase activity is associated with a greater reduction in RBF with ipsilateral UUO. To determine whether the stimulation of soluble guanylyl cyclase differs between glomeruli from obstructed kidneys and normal kidneys, cGMP was measured after stimulation by 10(-3) M sodium nitroprusside (SNP) in glomeruli isolated from the kidneys of Sprague-Dawley rats after 24 h of UUO or sham operation. The generation of intracellular and extracellular (EC) cGMP (femtomoles of cGMP/100 glomeruli/per hour) was measured by RIA. After incubation with SNP, the EC accumulation of cGMP by UUO glomeruli was significantly greater than that by glomeruli from sham-operated rats (P < 0.05). When glomerular studies were repeated in the presence of the phosphodiesterase inhibitor isobutyl methylxanthine, there was no difference in the EC accumulation of cGMP. The direct measurement of cGMP hydrolysis by phosphodiesterase was significantly less in glomerular homogenate from UUO rats compared with sham-operated rats (P < 0.05). When 10(-5) M losartan, an angiotensin II receptor inhibitor, was included in glomerular incubations, there was a significant decrease in the EC glomerular cGMP response to SNP in UUO glomeruli (P < 0.05). This attenuated response was abolished by the addition of isobutyl methylxanthine. The addition of angiotensin II did not alter the accumulation of cGMP by UUO or sham glomeruli. These studies indicate that decreased phosphodiesterase activity in UUO glomeruli contributes to the enhanced accumulation of EC glomerular cGMP after the stimulation of soluble guanylyl cyclase by SNP. In addition, angiotensin II receptors modulate this response, suggesting a role for soluble guanylyl cyclase in countering angiotensin-mediated vasoconstriction due to UUO.
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Igarashi, Kei M., and Kensaku Mori. "Spatial Representation of Hydrocarbon Odorants in the Ventrolateral Zones of the Rat Olfactory Bulb." Journal of Neurophysiology 93, no. 2 (February 2005): 1007–19. http://dx.doi.org/10.1152/jn.00873.2004.
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The glomerular sheet of the olfactory bulb (OB) forms odorant receptor maps that are parceled into zones. We previously reported the molecular receptive range (MRR) property of individual glomeruli in the dorsal zone (zone 1) of the OB and showed that polar functional groups play a major role in activating glomeruli in this zone. However, the MRR property of glomeruli in zones 2–4 is not well understood yet. Using the method of intrinsic signal imaging, we recorded odorant-induced glomerular activity from the ventrolateral surface (zones 2–4) of rat OB. While hydrocarbon odorants that lack polar functional groups activate only a few glomeruli in zone 1, we found that a series of hydrocarbon odorants consistently activated many glomeruli in the ventrolateral surface. The hydrocarbon-responsive glomeruli were grouped into two clusters; glomeruli in one cluster (cluster H) responded to benzene-family hydrocarbons but not to cyclic terpene hydrocarbons. Glomeruli in the other cluster (cluster I) responded to both classes of hydrocarbons. Detailed analyses of MRR properties of individual glomeruli using hydrocarbon odorants and polar-functional-group-containing odorants showed that the common and characteristic molecular features effective in activating glomeruli in the clusters H and I are the hydrocarbon skeleton. These results suggest that ORs represented by glomeruli in these clusters recognize primarily the hydrocarbon skeleton of odorants, and thus imply a systematic difference in the manner of recognizing odorant molecular features between ORs in zone 1 and ORs in zones 2–4.
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Gubhaju, Lina, Megan R. Sutherland, Bradley A. Yoder, Anthony Zulli, John F. Bertram, and M. Jane Black. "Is nephrogenesis affected by preterm birth? Studies in a non-human primate model." American Journal of Physiology-Renal Physiology 297, no. 6 (December 2009): F1668—F1677. http://dx.doi.org/10.1152/ajprenal.00163.2009.
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Nephrogenesis occurs predominantly in late gestation at a time when preterm infants are already delivered. The aims of this study were to assess the effect of preterm birth and the effect of antenatal glucocorticoid treatment on nephrogenesis. Preterm baboons, which were delivered at 125 days gestation and ventilated for up to 21 days postnatally, were compared with gestational controls. A cohort of preterm baboons that had been exposed to antenatal glucocorticoids were compared with unexposed preterm baboons. The number of glomerular generations was estimated using a medullary ray glomerular-counting method, and glomerular number was estimated using unbiased stereology. CD31 and WT-1 localization was examined using immunohistochemistry and VEGF was localized using in situ hybridization. The number of glomerular generations was not affected by preterm birth, and total glomerular numbers were within the normal range. Kidneys were significantly enlarged in preterm baboons with a significant decrease in glomerular density (number of glomeruli per gram of kidney) in the preterm kidney compared with gestational controls. Neonates exposed to antenatal steroids had an increased kidney-to-body weight ratio and also more developed glomeruli compared with unexposed controls. Abnormal glomeruli, with a cystic Bowman's space and shrunken glomerular tuft, were often present in the superficial renal cortex of both the steroid-exposed and unexposed preterm kidneys; steroid exposure had no significant effect on the proportion of abnormal glomeruli. The proportion of abnormal glomeruli in the preterm kidneys ranged from 0.2 to 18%. In conclusion, although nephrogenesis is ongoing in the extrauterine environment, our findings demonstrate that preterm birth, independent of steroid exposure, is associated with a high proportion of abnormal glomeruli in some, but not all neonatal kidneys. Whether final nephron endowment is affected in those kidneys exhibiting a high proportion of abnormal glomeruli is yet to be confirmed.
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Kakimoto, Tetsuhiro, Kinya Okada, Yoshihiro Hirohashi, Raissa Relator, Mizue Kawai, Taku Iguchi, Keisuke Fujitaka, et al. "Automated image analysis of a glomerular injury marker desmin in spontaneously diabetic Torii rats treated with losartan." Journal of Endocrinology 222, no. 1 (April 29, 2014): 43–51. http://dx.doi.org/10.1530/joe-14-0164.
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Diabetic nephropathy is a major complication in diabetes and a leading cause of end-stage renal failure. Glomerular podocytes are functionally and structurally injured early in diabetic nephropathy. A non-obese type 2 diabetes model, the spontaneously diabetic Torii (SDT) rat, is of increasing preclinical interest because of its pathophysiological similarities to human type 2 diabetic complications including diabetic nephropathy. However, podocyte injury in SDT rat glomeruli and the effect of angiotensin II receptor blocker treatment in the early stage have not been reported in detail. Therefore, we have evaluated early stages of glomerular podocyte damage and the beneficial effect of early treatment with losartan in SDT rats using desmin as a sensitive podocyte injury marker. Moreover, we have developed an automated, computational glomerulus recognition method and illustrated its specific application for quantitatively studying glomerular desmin immunoreactivity. This state-of-the-art method enabled automatic recognition and quantification of glomerular desmin-positive areas, eliminating the need to laboriously trace glomerulus borders by hand. The image analysis method not only enabled assessment of a large number of glomeruli, but also clearly demonstrated that glomerular injury was more severe in the juxtamedullary region than in the superficial cortex region. This applied not only in SDT rat diabetic nephropathy but also in puromycin aminonucleoside-induced nephropathy, which was also studied. The proposed glomerulus image analysis method combined with desmin immunohistochemistry should facilitate evaluations in preclinical drug efficacy studies as well as elucidation of the pathophysiology of diabetic nephropathy.
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Comper, W. D., A. S. N. Lee, M. Tay, and Y. Adal. "Anionic charge concentration of rat kidney glomeruli and glomerular basement membrane." Biochemical Journal 289, no. 3 (February 1, 1993): 647–52. http://dx.doi.org/10.1042/bj2890647.
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Estimates of levels of glomerular and glomerular-basement-membrane anion charge should serve as useful quantitative markers for the integrity of the tissues in health and disease. We have developed a simple, rapid, technique to measure this charge through the use of ion exchange with radioisotopes 22Na+ and 36Cl- at low ionic strengths in phosphate buffer. When this technique is used, normal glomeruli isolated from rat have a measured net anion charge concentration of 17.4 +/- 3.7 p-equiv. per glomerulus (n = 20). Perfused rat kidneys that lose approximately half of their glomerular heparan [35S]sulphate content (owing to oxygen-radical damage) exhibited a lower anion charge, of 7.5 +/- 1.6 p-equiv. per glomerulus (n = 5). Glomerular basement membranes prepared from rat glomeruli by a sonication-centrifugation procedure in the presence of enzyme inhibitors had a charge concentration of 6.3 +/- 0.7 mu-equiv./g wet wt. of tissue (n = 4), whereas membranes prepared by sonication, centrifugation, DNAse and detergent treatment had a charge concentration of 7.1 +/- 1.6 mu-equiv./g wet wt. (n = 4). Isotope-dilution experiments with 3H2O on these detergent-prepared glomerular basement membranes demonstrated that they had a water content of approx. 93%, which would then give a net anion charge concentration of 7.6 +/- 1.7 m-equiv./l (n = 4). These values are in good agreement with those obtained by others using titration techniques [Bray and Robinson (1984) Kidney Int. 25, 527-533]. The relatively low magnitude of glomerular anion charge in normal kidneys is consistent with other recent findings that glomerular anion charge is too low to affect the glomerular transport of charged molecules in a direct, passive, biophysical manner through electrostatic interactions.
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Dasari, Surendra, Mariam P. Alexander, Julie A. Vrana, Jason D. Theis, John R. Mills, Vivian Negron, Sanjeev Sethi, et al. "DnaJ Heat Shock Protein Family B Member 9 Is a Novel Biomarker for Fibrillary GN." Journal of the American Society of Nephrology 29, no. 1 (November 2, 2017): 51–56. http://dx.doi.org/10.1681/asn.2017030306.
Full textAbstract:
Fibrillary GN (FGN) is a rare primary glomerular disease. Histologic and histochemical features of FGN overlap with those of other glomerular diseases, and no unique histologic biomarkers for diagnosing FGN have been identified. We analyzed the proteomic content of glomeruli in patient biopsy specimens and detected DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) as the fourth most abundant protein in FGN glomeruli. Compared with amyloidosis glomeruli, FGN glomeruli exhibited a >6-fold overexpression of DNAJB9 protein. Sanger sequencing and protein sequence coverage maps showed that the DNAJB9 protein deposited in FGN glomeruli did not have any major sequence or structural alterations. Notably, we detected DNAJB9 in all patients with FGN but not in healthy glomeruli or in 19 types of non-FGN glomerular diseases. We also observed the codeposition of DNAJB9 and Ig-γ. Overall, these findings indicate that DNAJB9 is an FGN marker with 100% sensitivity and 100% specificity. The magnitude and specificity of DNAJB9 overabundance in FGN also suggests that this protein has a role in FGN pathogenesis. With this evidence, we propose that DNAJB9 is a strong biomarker for rapid diagnosis of FGN in renal biopsy specimens.
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Dakovic-Bjelakovic, Marija, Vojin Savic, Slobodan Vlajkovic, and Tanja Dzopalic. "Development and ultrastructure of glomerular capillaries in human foetus." Srpski arhiv za celokupno lekarstvo 136, Suppl. 4 (2008): 316–22. http://dx.doi.org/10.2298/sarh08s4316d.
Full textAbstract:
Glomerulus is an important filtrating apparatus in the body. Three types of cells - endothelial, mesangial and visceral epithelial cells can be identified in the capillary tuft. Glomeruli develop during nephrogenesis which starts in the 8th week and ends between the 32nd and 36th week of gestation. The nephron develops through stages described as the vesicle, the comma-shaped, S-shaped with the developing glomerulus and the mature glomerulus. Glomerular differentiation involves the expansion of the original capillary component into the plexus that consists of 6-8 loops and the migration of podocytes that are arranged around these glomerular capillaries. Glomerular capillary differentiation represents a set of developmental changes of the glomerular endothelial and epithelial cells. The active differentiation of glomerular capillaries starts in the hemisphere of an inferior arm of S-shaped bodies. Endothelial precursors unite into precapillaries devoid of lumen. Further differentiation includes the flattening of endothelial cells on the basement membrane, the loss of superfluous cells, the development of lumen and the formation of fenestrae. The glomerular basement membrane is differentiated by the fusion of epithelial and endothelial basement membrane. The differentiation of visceral epithelial cells includes the development of cytoplasmic processes and the flattening of cell bodies. Primary cytoplasmic processes are formed from the podocyte bodies and develop secondary and tertiary processes or foot processes. Foot processes from one podocyte interdigitate with foot processes from other podocytes. In the developing glomeruli, there is a difference in the level of differentiation of visceral epithelial cells. Cells with differentiated foot processes and cells with no cytoplasmic processes are observed within the same glomerulus.
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Buonviso, N., and M. A. Chaput. "Response similarity to odors in olfactory bulb output cells presumed to be connected to the same glomerulus: electrophysiological study using simultaneous single-unit recordings." Journal of Neurophysiology 63, no. 3 (March 1, 1990): 447–54. http://dx.doi.org/10.1152/jn.1990.63.3.447.
Full textAbstract:
1. The glomeruli of the olfactory bulb are discrete anatomic structures in which the terminals of receptor cell axons make extensive contacts with the primary dendrites of the mitral and tufted output cells. In mammals, each mitral and deep tufted (M/T) cell possesses a single primary dendrite and sends it toward the glomerulus situated just in front of its somata. 2. We tested the hypothesis that the glomeruli, which appear to form anatomic units, could act to some extent as functional units. A unitary functioning implies that the M/T cells connected to the same glomerulus will more often display similar responses to odorants than cells having no common glomerular relationships, including cells related to adjacent glomeruli. 3. In anesthetized adult rats, we recorded the extracellular single-unit responses of pairs of M/T cells to a series of five odorants. Recordings were performed with the use of twin microelectrodes whose tips were separated either by less than 40 or by 150-200 microns. Because of the olfactory bulb organization, we assumed that the close cells, recorded at a distance less than 40 microns, were more often connected to the same glomerulus, whereas the distant cells, recorded at a distance of 150-200 microns, were more often connected to adjacent glomeruli. 4. Stimulus-evoked changes in firing rate were classified as either excitatory (+), suppressive (-), or null (0) responses. The collection of response types of a given cell to the 5 odorants composed its response profile. Response profiles were used to compare the responsiveness within close and within distant cell pairs with that observed within control pairs of cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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Baricos, W. H., S. Cortez-Schwartz, and S. V. Shah. "Renal neuraminidase. Characterization in normal rat kidney and measurement in experimentally induced nephrotic syndrome." Biochemical Journal 239, no. 3 (November 1, 1986): 705–10. http://dx.doi.org/10.1042/bj2390705.
Full textAbstract:
Several lines of evidence suggest that increased neuraminidase activity may be responsible for the loss of glomerular N-acetylneuraminic acid (AcNeu) observed in various glomerular diseases. However, virtually no information is available on the activity of neuraminidase in glomeruli or the potential role of this enzyme in glomerular pathophysiology. Utilizing 2′-(4-methylumbelliferyl)-alpha-D-N-acetylneuraminic acid (4MU-AcNeu) as substrate, we defined optimal assay conditions and characterized neuraminidase activity in glomeruli and, for comparison, in other renal fractions and liver. Neuraminidase activity in glomeruli, cortex and tubules was maximal at pH 4.4. The Km for 4MU-AcNeu was estimated to be 195 microM for glomeruli and 226 microM for cortex. Glomerular neuraminidase was inhibited by AcNeu (90% at 25 mM) and high concentrations of Triton X-100 (26% at 0.5%), but unaffected by CaCl2, EDTA or N-ethylmaleimide (each 1 mM). Neuraminidase activity (nmol/h per mg of protein; mean +/- S.E.M.) in normal rat kidney was: cortex, 14.47 +/- 0.76; medulla, 7.85 +/- 0.64; papilla, 2.64 +/- 0.11; tubules, 13.79 +/- 0.70; glomeruli, 5.57 +/- 0.28. In comparison, neuraminidase activity in rat liver was 2.58 +/- 0.14. Puromycin aminonucleoside (PAN)-induced nephrotic syndrome is a model of glomerular disease in which the loss of glomerular AcNeu is well documented. In two separate studies, we observed no change in the specific activity of neuraminidase in either glomeruli or cortex isolated from rats treated with PAN (15 mg/100 g, intraperitoneally) and killed at either the onset or the peak of proteinuria. Results were similar whether neuraminidase activity was expressed per mg of protein or per microgram of DNA.
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Brown, J., S. P. Salas, A. Singleton, J. M. Polak, and C. T. Dollery. "Autoradiographic localization of atrial natriuretic peptide receptor subtypes in rat kidney." American Journal of Physiology-Renal Physiology 259, no. 1 (July 1, 1990): F26—F39. http://dx.doi.org/10.1152/ajprenal.1990.259.1.f26.
Full textAbstract:
The distribution of atrial natriuretic peptide (ANP) clearance receptors in rat kidney was investigated by in vitro autoradiography using des[Gln18,Ser19,Gly20,Leu21,Gly22]-ANP-(4- 23) (C-ANP) and 125I-Tyr0-ANP-(5-25) as relatively specific ligands of this receptor. Alpha-125I-ANP (100 pM) bound reversibly but with high affinity to glomeruli, outer medullary vasa recta bundles, and inner medulla. C-ANP (10 microM) inhibited greater than 60% of this glomerular binding but did not inhibit the binding of alpha-125I-ANP to medullary tissues. Alpha-125I-ANP also bound reversibly to the renal arteries up to the glomerulus. This arterial binding was only partly inhibited by 10 microM C-ANP. In the presence of 10 microM C-ANP, increasing concentrations of alpha-125I-ANP bound to a residue of glomerular sites with apparent dissociation constants of 0.82 +/- 0.16 to 2.73 +/- 1.20 nM at different cortical levels. 125I-Tyr0-ANP-(5-25) bound significantly to glomeruli and intrarenal arteries but not to vasa recta bundles or inner medulla. This glomerular binding also occurred with nanomolar dissociation constants. It was completely inhibited by 1 microM alpha-ANP and 10 microM C-ANP, but not by unrelated peptides such as gastrin. These results suggest that renal ANP clearance receptors are restricted in vivo to the glomeruli and renal arterial system of the rat.
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HUANG, XIOU RU, A. RICHARD KITCHING, PETER G. TIPPING, and STEPHEN R. HOLDSWORTH. "Interleukin-10 Inhibits Macrophage-Induced Glomerular Injury." Journal of the American Society of Nephrology 11, no. 2 (February 2000): 262–69. http://dx.doi.org/10.1681/asn.v112262.
Full textAbstract:
The ability of interleukin-10 (IL-10) to inhibit macrophage recruitment, activation, and proliferation in vivo was studied in a macrophage-mediated, but T cell-independent, passive anti-glomerular basement membrane antibody-induced model of glomerulonephritis (GN) in rats. Treatment with recombinant murine IL-10 resulted in dose-dependent reductions in proteinuria (high dose: 16 ± 1 mg/24 h; low dose: 30 ± 2 mg/24 h; control treatment: 69 ± 6 mg/24 h; normal: 7 ± 1 mg/24 h) and glomerular macrophage recruitment (high dose: 1.8 ± 0.1 macrophages per glomerular cross section [c/gcs]; low dose: 5.5 ± 0.2 c/gcs; control treatment: 12.1 ± 0.6 c/gcs). Macrophage and intrinsic glomerular cell proliferation were reduced at both doses of IL-10, as was glomerular expression of P-selectin and monocyte chemoattractant protein-1. IL-10 treatment also resulted in a dose-dependent reduction of macrophage activation as indicated by MHC class II and IL-1β expression. Glomerular nitrite production by isolated cultured glomeruli was reduced after IL-10 treatment in vivo (high dose: 2.3 ± 2.3 nmol/104 glomeruli per 72 h; low dose: 28 ± 5 nmol/104 glomeruli per 72 h; control treatment: 82 ± 11 nmol/104 glomeruli per 72 h). Tumor necrosis factor-α production was abolished by high-dose treatment and reduced by the lower dose (3.8 ± 3.8 pg/104 glomeruli per 72 h; control treatment: 249 ± 23 pg/104 glomeruli per 72 h). These studies demonstrate that IL-10 directly attenuates glomerular macrophage recruitment, activation, and proliferation in vivo and can significantly attenuate macrophage-mediated GN independent of any effects on T cells.
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Wang, Jun-Ling, Hui-Fang Cheng, Ming-Zhi Zhang, James A. McKanna, and Raymond C. Harris. "Selective increase of cyclooxygenase-2 expression in a model of renal ablation." American Journal of Physiology-Renal Physiology 275, no. 4 (October 1, 1998): F613—F622. http://dx.doi.org/10.1152/ajprenal.1998.275.4.f613.
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Previous studies have suggested a possible role for prostaglandins (PGs) in mediating alterations in nephron structure and function ensuing after renal ablation. Two isoforms of cyclooxygenase (COX) have been described: constitutive (COX-1) and inducible (COX-2). We examined expression of these isoforms following subtotal renal ablation (5/6 ablation, RA) in rats. In renal cortex, COX-2 mRNA and immunoreactive protein (IP) increased progressively compared with sham-operated littermates. In contrast, there were no significant changes in COX-1 mRNA expression. In normal kidney, cortical COX-1 IP was immunolocalized predominantly to mesangial cells and collecting tubules, whereas COX-2 IP was found in a subset of cortical thick ascending limb of Henle’s loop (CTAL) cells in the region of the macula densa (MD). Following RA, significantly increased COX-2 IP was detected in the MD and surrounding CTAL cells. In addition, fainter immunoreactive COX-2 was detected in scattered visceral epithelial cells and mesangial cells of the glomerulus. Immunoblotting of isolated glomeruli demonstrated a selective increase of glomerular immunoreactive COX-2 expression following RA. No change of COX-1 expression was seen. To determine COX activity, isolated glomeruli were incubated with arachidonic acid and PGE2 measured by enzyme immunoassay (EIA). Compared with sham, glomeruli from 2 wk RA produced significantly more PGs. SC-58560, a selective COX-1 inhibitor, did not inhibit PG production in the remnant glomeruli at concentrations up to 10−4 M, whereas SC-58236, a relatively selective COX-2 inhibitor, significantly inhibited PG production by RA glomeruli. In preliminary studies, to define mechanisms of altered expression of glomerular COX-2, rat mesangial cells were incubated with serum from sham or 2 wk RA. There were significant increases in COX-2 expression in response to 2 wk RA serum. In summary, these results indicate selective increases in renal cortical COX-2 expression following renal ablation.
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Yokoo, T., and M. Kitamura. "IL-1beta depresses expression of the 70-kilodalton heat shock protein and sensitizes glomerular cells to oxidant-initiated apoptosis." Journal of Immunology 159, no. 6 (September 15, 1997): 2886–92. http://dx.doi.org/10.4049/jimmunol.159.6.2886.
Full textAbstract:
Abstract The 70-kDa heat shock protein (hsp70) is induced by several physical stimuli, whereas little is understood about the regulation and function of this molecule during inflammation. We found that the proinflammatory cytokine IL-1beta depressed hsp70 expression in glomerular mesangial cells and that IL-1-pretreated cells were more susceptible to apoptotic death triggered by oxidant stress. To examine whether the altered expression of hsp70 causes the effect of IL-1beta on apoptosis, rat mesangial cells were stably transfected with a hsp70 cDNA under the control of a constitutively active regulatory element. Compared with mock-transfected cells, the established cells overexpressing hsp70 showed resistance to the effect of IL-1beta. The effects of IL-1beta on hsp70 expression and apoptosis were also examined in isolated rat glomeruli. Consistent with the results from mesangial cells, IL-1beta repressed the expression of hsp70 and enhanced the oxidant-initiated apoptosis in the glomerulus. The relationship between glomerular hsp70 and apoptosis was further investigated using an experimental model of anti-glomerular basement membrane glomerulonephritis in which IL-1 and oxidants play crucial roles. Compared with normal expression, the expression of hsp70 was significantly reduced in the inflamed glomeruli. Furthermore, the nephritic glomeruli exhibited oligonucleosomal DNA fragmentation typical of apoptosis. These findings suggested a novel mechanism by which IL-1 may induce glomerular injury. IL-1beta has the potency to affect intrinsic cytoprotective machinery and thereby sensitizes glomerular cells to oxidant-initiated apoptosis. We identified hsp70 as a potential molecular target in this process.
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Porush, Jerome G., and Pierre F. Faubert. "Renal disease in elderly patients." Reviews in Clinical Gerontology 7, no. 4 (November 1997): 299–307. http://dx.doi.org/10.1017/s0959259897007430.
Full textAbstract:
Like other organs in the body, the kidneys undergo age-associated anatomical, structural and physiological changes. Starting at 50 years of age, there is a 3-10% decline in kidney weight for each subsequent decade of life, with the loss of cortical mass greater than medullary mass. In fact, the number of glomeruli start to decrease progressively after age 40, and the number of sclerotic glomeruli increases, making the distinction between involutional and disease-related sclerosis unclear in some cases. The outer cortical glomeruli are, in general, more extensively involved than deeper glomeruli, but glomerular size does not change. In general, the loss of the glomerular mass is proportional to the loss of tubular mass, maintaining glomerulotubular balance. In addition to glomerular sclerosis, there is a gradual increase in interstitial fibrosis, and there is focal thickening of both glomerular and tubular basement membranes, probably due to the accumulation of type IV collagen.
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Hayakawa, Kunihiro, Yiman Meng, Nobuhiko Hiramatsu, Ayumi Kasai, Jian Yao, and Masanori Kitamura. "Spontaneous activation of the NF-κB signaling pathway in isolated normal glomeruli." American Journal of Physiology-Renal Physiology 291, no. 6 (December 2006): F1169—F1176. http://dx.doi.org/10.1152/ajprenal.00513.2005.
Full textAbstract:
In this report, we describe that NF-κB is spontaneously activated in isolated, normal glomeruli. Ex vivo incubation of isolated rat glomeruli triggered expression of a NF-κB-dependent gene, monocyte chemoattractant protein-1 (MCP-1), in parallel with downregulation of IκBα and IκBβ proteins and activation of the p65 NF-κB subunit. The induction of MCP-1 was also observed in mesangial cells coincubated with isolated glomeruli or exposed to media conditioned by isolated glomeruli (GCM), which was abrogated by inhibition of NF-κB. The activation of NF-κB by glomerulus-derived factors was confirmed using reporter mesangial cells that produce secreted alkaline phosphatase (SEAP) under the control of the κB enhancer element. When the reporter cells were adoptively transferred into normal glomeruli, expression of SEAP mRNA and activity of SEAP were also upregulated in the explanted glomeruli. The molecular weight of factors responsible for activation of NF-κB was >50 kDa, and TNF-α was identified as one of glomerulus-derived activators. To examine upstream events involved, we focused on MAP kinases that are spontaneously activated in explanted glomeruli. Selective suppression of ERK or p38 MAP kinase significantly attenuated activation of NF-κB in mesangial cells triggered by coculture with isolated glomeruli. Interestingly, the suppressive effects by MAP kinase inhibitors were not observed in mesangial cells treated with GCM. These data suggested that NF-κB was spontaneously activated in explanted glomeruli via autocrine/paracrine factors including TNF-α and that the production of NF-κB activators by glomeruli was, at least in part, through MAP kinase pathways.
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Kitching, A. Richard, Joshua Ooi, Janet Chang, and Stephen Holdsworth. "The immunodominant CD4+ T cell epitope of myeloperoxidase induces cell mediated injury in murine anti-myeloperoxidase glomerulonephritis (159.14)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 159.14. http://dx.doi.org/10.4049/jimmunol.188.supp.159.14.
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Abstract Microscopic polyangiitis, characterized by pathogenic autoantibodies to neutrophil cytoplasmic proteins (ANCA), including myeloperoxidase (MPO), frequently targets the glomerulus. Although the pathogenicity of ANCA has been established, the role of CD4+ cells, cell mediated effector responses and MPO T cell epitopes are not known. By screening overlapping peptides of 20aa spanning the entire MPO molecule, we identified an immunodominant MPO CD4+ cell epitope (MPO409-428). Immunization with MPO409-428 induced disease similar to that seen with whole MPO when disease was triggered with anti-glomerular basement membrane antibodies. A CD4+ MPO409-428 specific clone transferred into Rag1-/- mice induced necrotizing glomerulonephritis with renal impairment when MPO409-428 was planted in glomeruli, or when whole MPO was deposited in glomeruli after neutrophil recruitment induced by transfer of anti-MPO antibodies with LPS. MPO409-428 also induced biologically active anti-MPO antibodies in mice. The MPO409-428 T cell epitope has a minimum immunogenic core region of 11 aa, MPO415-426, with several critical residues. These studies identify an immunodominant MPO T cell epitope and redefine how effector responses induce injury in MPO-ANCA associated microscopic polyangiitis. ANCA activate neutrophils not only induce injury, but also lodge the autoantigen MPO in glomeruli, where autoreactive CD4+ cells act to induce delayed-type hypersensitivity like necrotizing glomerular lesions.
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Satchell, Simon C., Steve J. Harper, John E. Tooke, Dontscho Kerjaschki, Moin A. Saleem, and Peter W. Mathieson. "Human Podocytes Express Angiopoietin 1, a Potential Regulator of Glomerular Vascular Endothelial Growth Factor." Journal of the American Society of Nephrology 13, no. 2 (February 2002): 544–50. http://dx.doi.org/10.1681/asn.v132544.
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ABSTRACT. Vascular endothelial growth factor (VEGF) is abundantly expressed by podocytes, but its role in glomeruli is unknown. Angiopoietins are endothelial cell growth factors that function in concert with VEGF but have not previously been observed in human glomeruli. Angiopoietin 1 (Ang1) acts via the endothelial receptor Tie2 to promote maturation and stabilization of blood vessels, resisting angiogenesis and opposing some actions of VEGF. Ang1, Ang2, Tie2, and VEGF expression in normal human renal cortex was examined with immunofluorescence and immunohistochemical analyses. High-power, multiple-color, immunofluorescence analyses and additional antibodies (specific for particular components of the glomerular filtration barrier) were used to determine the exact locations of Ang1 and Tie2 in the glomerular capillary wall. Immuno-electron-microscopic analysis of rat glomeruli was used to further localize endothelial Tie2 expression. RNA and protein extracted from human glomeruli, cultured human podocytes, and cultured human endothelial cells were analyzed for Ang1, Ang2, and Tie2 by using reverse transcription-PCR and Western blotting. Ang1 was detected in podocytes in normal glomeruli and, with VEGF, was concentrated in podocyte foot processes. Tie2 was demonstrated on glomerular capillary endothelial cells, particularly on the abluminal surface. Reverse transcription-PCR and Western blotting analyses confirmed the expression of Ang1 and Tie2 in glomeruli and of Ang1 in cultured podocytes. These findings suggest a role for Ang1 in the maintenance of the glomerular endothelium and make it a good candidate to be a regulator of the actions of VEGF on glomerular permeability, resisting angiogenesis while allowing the induction of high permeability to water and small solutes.
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Robert, B., P. L. St John, D. P. Hyink, and D. R. Abrahamson. "Evidence that embryonic kidney cells expressing flk-1 are intrinsic, vasculogenic angioblasts." American Journal of Physiology-Renal Physiology 271, no. 3 (September 1, 1996): F744—F753. http://dx.doi.org/10.1152/ajprenal.1996.271.3.f744.
Full textAbstract:
Renal glomerular capillary tufts have been believed to arise from angiogenic ingrowth of extrinsic vessels. We found, however, that when embryonic day 12 (E12) mouse kidneys were maintained in culture for 6 days and then grafted into anterior eye chambers of adult transgenic ROSA26 host mice (which carry the beta-galactosidase transgene), glomerular endothelial cells within the grafts were predominantly of intrinsic, kidney origin. To identify potential endothelial precursors, we immunolabled kidneys with antibodies against the vascular endothelial growth factor receptor, flk-1. Numerous discrete cells expressing flk-1 were scattered throughout the nephrogenic mesenchyme of both E12 and newborn kidneys, and with development these cells became concentrated in microvessels, glomerular vascular clefts, and glomerular tufts. In adults, flk-1 was weakly expressed in glomeruli but absent elsewhere. To examine abilities of flk-1-positive cells to establish glomeruli, E12 kidneys were grafted into kidney cortices of adult and newborn ROSA26 hosts. Grafts into adults resulted in few glomeruli containing host-derived endothelium, whereas a majority of glomeruli grafted into newborns contained host cells. Cells of graft origin were found in vessels forming in renal cortices of newborn hosts, but not in adults. Our findings indicate that embryonic kidney cells expressing flk-1 are angioblasts that create microvessels and glomeruli by vasculogenesis.
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Schlondorff, D., P. Goldwasser, R. Neuwirth, J. A. Satriano, and K. L. Clay. "Production of platelet-activating factor in glomeruli and cultured glomerular mesangial cells." American Journal of Physiology-Renal Physiology 250, no. 6 (June 1, 1986): F1123—F1127. http://dx.doi.org/10.1152/ajprenal.1986.250.6.f1123.
Full textAbstract:
Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) results in contraction of isolated glomeruli and cultured mesangial cells and concomitantly causes release of arachidonic acid and prostaglandin E2 (PGE2) formation. The kidney and isolated glomeruli can also generate material that has PAF bioactivity. We therefore examined the capacity of isolated renal glomeruli and cultured glomerular mesangial cells from rats to form PAF. Both isolated glomeruli and cultured mesangial cells transformed 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine ([3H]lyso-PAF) into a labeled product comigrating both on thin-layer chromatography (TLC) and high-pressure liquid chromatography (HPLC) with authentic PAF. Using rabbit platelet aggregation as bioassay for PAF, we found that isolated glomeruli produced 4 +/- 2 pmol/mg glomerular protein of PAF-like material, and mesangial cells produced 30 +/- 8 pmol/mg cell protein when stimulated with A23187 (10(-5) M) for 30 min. The major species of the PAF material produced by mesangial cells was identified as 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine after HPLC separation, followed by fast atom bombardment and gas chromatography-mass spectrometry. These results show that glomerular mesangial cells can produce PAF, which could contribute locally to the regulation of glomerular function.