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1
Dominguez, J. H., M. Juhaszova, S. B. Kleiboeker, C. C. Hale, and H. A. Feister. "Na(+)-Ca2+ exchanger of rat proximal tubule: gene expression and subcellular localization." American Journal of Physiology-Renal Physiology 263, no. 5 (November 1, 1992): F945—F950. http://dx.doi.org/10.1152/ajprenal.1992.263.5.f945.
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The activity of the Na(+)-Ca2+ exchanger, a membrane transporter that mediates Ca2+ efflux, has been described in amphibian and mammalian renal proximal tubules. However, demonstration of cell-specific expression of the Na(+)-Ca2+ exchanger in proximal renal tubules has been restricted to functional assays. In this work, Na(+)-Ca2+ exchanger gene expression in rat proximal tubules was characterized by three additional criteria: functional assay of transport activity in membrane vesicles derived from proximal tubules, expression of specific Na(+)-Ca2+ exchanger protein detected on Western blots, and determination of specific mRNA encoding Na(+)-Ca2+ exchanger protein on Northern blots. A new transport activity assay showed that proximal tubule membranes contained the highest Na(+)-Ca2+ exchanger transport activity reported in renal tissues. In dog renal proximal tubules and sarcolemma, a specific protein of approximately 70 kDa was detected, whereas in rat proximal tubules and sarcolemma, the specific protein approximated 65 kDa and was localized to the basolateral membrane. On Northern blots, a single 7-kb transcript isolated from rat proximal tubules, whole kidney, and heart hybridized under high-stringency conditions with rat heart cDNA. These data indicate that Na(+)-Ca2+ exchanger protein expressed in rat proximal tubule is similar, if not identical, to the cardiac protein. We suggest that the tubular Na(+)-Ca2+ exchanger characterized herein represents the Na(+)-Ca2+ exchanger described in functional assays of renal proximal tubules.
2
Ramachandran, C., and M. G. Brunette. "The renal Na+/Ca2+ exchange system is located exclusively in the distal tubule." Biochemical Journal 257, no. 1 (January 1, 1989): 259–64. http://dx.doi.org/10.1042/bj2570259.
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The movement of Ca2+ across the basolateral plasma membrane was determined in purified preparations of this membrane isolated from rabbit proximal and distal convoluted tubules. The ATP-dependent Ca2+ uptake was present in basolateral membranes from both these tubular segments, but the activity was higher in the distal tubules. A very active Na+/Ca2+ exchange system was also demonstrated in the distal-tubular membranes, but in proximal-tubular membranes this exchange system was not demonstrable. The presence of Na+ outside the vesicles gradually inhibited the ATP-dependent Ca2+ uptake in the distal-tubular-membrane preparations, but remained without effect in those from the proximal tubules. The activity of the Na+/Ca2+ exchange system in the distal-tubular membranes was a function of the imposed Na+ gradient. These results suggest that the major differences in the characteristics of Ca2+ transport in the proximal and in the distal tubules are due to the high activity of a Na+/Ca2+ exchange system in the distal tubule and its virtual absence in the proximal tubule.
3
Beyenbach, Klaus W. "Kidneys sans glomeruli." American Journal of Physiology-Renal Physiology 286, no. 5 (May 2004): F811—F827. http://dx.doi.org/10.1152/ajprenal.00351.2003.
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The evolution of the vertebrate kidney records three occasions, each separated by about 50 million years, when fish have abandoned glomeruli to produce urine by tubular mechanisms. The recurring dismissal of glomeruli suggests a mechanism of aglomerular urine formation intrinsic to renal tubules. Indeed, the transepithelial secretion of organic solutes and of inorganic solutes such as sulfate, phosphate, and magnesium can all drive secretory water flow in renal proximal tubules of fish. However, the secretion of NaCl via secondary active transport of Cl is the primary mover of secretory water flow in, surprisingly, proximal tubules of both glomerular and aglomerular fish. In filtering kidneys, the tubular secretion of solute and water is overshadowed by reabsorptive transport activities, but secretion progressively comes to light as glomerular filtration decreases. Thus the difference between glomerular and aglomerular urine formation is more a difference of degree than of kind. At low rates of glomerular filtration in seawater fish, NaCl-coupled water secretion serves to increase the renal excretory capacity by increasing the luminal volume into which waste, excess, and toxic solutes can be secreted. The reabsorption of NaCl and water in the distal nephron and urinary bladder concentrates unwanted solutes for excretion while minimizing renal water loss. In aglomerular fish, NaCl-coupled water secretion across proximal tubules replaces glomerular filtration to increase renal excretory capacity. A review of the literature suggests that tubular secretion of NaCl and water is an early function of the vertebrate proximal tubule that has been retained throughout evolution. Active transepithelial Cl secretion takes place in gall bladders studied as models of the mammalian proximal tubule and in proximal tubules of amphibians and apparently also of mammals. The tubular secretion of Cl is also observed in mammalian distal tubules. The evidence consistent with and for Cl secretion in, respectively, proximal and distal tubules of the mammalian kidney calls for a reexamination of basic assumptions in renal physiology that may lead to new opportunities for managing some forms of renal disease.
4
Miller, D. S. "Daunomycin secretion by killfish renal proximal tubules." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 269, no. 2 (August 1, 1995): R370—R379. http://dx.doi.org/10.1152/ajpregu.1995.269.2.r370.
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Epifluorescence microscopy and video-image analysis were used to measure the uptake of the fluorescent anthracycline daunomycin by intact killifish renal proximal tubules. When tubules were incubated in medium containing 2-5 microM daunomycin, the drug accumulated in the cells and the tubular lumen. At steady state, luminal fluorescence was two to three times greater than cellular fluorescence. Luminal accumulation of daunomycin was reduced when tubules were exposed to the multidrug-resistance (MDR) transporter modifiers verapamil and cyclosporin A (CSA), but not tetraethylammonium (TEA), a model substrate for the renal organic cation transport system. NaCN and vanadate reduced luminal drug accumulation. In contrast, cellular daunomycin accumulation was not affected by verapamil, CSA, TEA, or vanadate and was only slightly reduced by NaCN. When the pH of the buffer solution was decreased from 8.25 to 7.25, luminal, but not cellular, accumulation of daunomycin was again reduced by CSA; however, TEA now reduced cellular and luminal accumulation. These findings are consistent with daunomycin being actively secreted in killifish proximal tubule by two mechanisms. At pH 8.25, daunomycin crossed the basolateral membrane by simple diffusion and was secreted into the tubular lumen by the MDR transporter. At pH 7.25, daunomycin was transported across the basolateral membrane by simple diffusion and carrier-mediated uptake on the organic cation transporter and was secreted into the lumen by the MDR transporter and the organic cation/H+ exchanger.
5
Maurel, Agnès, Odile Spreux-Varoquaux, Francesco Amenta, Seyed Khosrow Tayebati, Daniele Tomassoni, Marie-Hélène Seguelas, Angelo Parini, and Nathalie Pizzinat. "Vesicular monoamine transporter 1 mediates dopamine secretion in rat proximal tubular cells." American Journal of Physiology-Renal Physiology 292, no. 5 (May 2007): F1592—F1598. http://dx.doi.org/10.1152/ajprenal.00514.2006.
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Renal dopamine, synthesized by proximal tubules, plays an important role in the regulation of renal sodium excretion. Although the renal dopaminergic system has been extensively investigated in both physiological and pathological situations, the mechanisms whereby dopamine is stored and secreted by proximal tubule cells remain obscure. In the present study we investigated whether vesicular monoamine transporters (VMAT)-1 and -2, which participate in amine storing and secretion, are expressed in rat renal proximal tubules, and we defined their involvement in dopamine secretion. By combining RT-PCR, Western blot, and immunocytochemistry we showed that VMAT-1 is the predominant isoform expressed in isolated proximal tubule cells. These results were confirmed by immunohistochemistry analysis of rat renal cortex showing that VMAT-1 was found in proximal tubules but not in glomeruli. Functional studies showed that, as previously reported for VMAT-dependent amine transporters, dopamine release by cultured proximal tubule cells was partially inhibited by disruption of intracellular H+ gradient. In addition, dopamine secretion was prevented by the VMAT-1/VMAT-2 inhibitor reserpine but not by the VMAT-2 inhibitor tetrabenazine. Finally, we demonstrated that tubular VMAT-1 mRNA and protein expression were significantly upregulated during a high-sodium diet. In conclusion, our results show for the first time the expression of a VMAT in the renal proximal tubule and its involvement in regulation of dopamine secretion. These data represent the first step toward the comprehension of the role of this transporter in renal dopamine handling and its involvement in pathological situations.
6
Miller, D. S., and J. B. Pritchard. "Nocodazole inhibition of organic anion secretion in teleost renal proximal tubules." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 267, no. 3 (September 1, 1994): R695—R704. http://dx.doi.org/10.1152/ajpregu.1994.267.3.r695.
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The impact of the microtubule-disrupting drug nocodazole on renal tubular secretion of organic anions was examined in vitro using proximal tubular masses from teleost fish. Nocodazole reversibly inhibited 20-30% of the tubular accumulation of two model organic anions, p-aminohippurate and fluorescein (FL), by winter flounder tubular masses. However, the drug had no effect on the initial rate of organic anion uptake. Thus it did not reduce transport into the cells at the basolateral membrane, either directly by affecting basolateral organic anion transport proteins or indirectly by altering metabolism or ion gradients. Instead, epifluorescence video microscopy and digital image analysis of killifish tubules showed that nocodazole greatly reduced luminal accumulation of FL and had a smaller effect on cellular dye accumulation. Luminal FL accumulation returned to control levels when tubules were incubated in drug-free medium. Confocal fluorescence microscopy confirmed the marked reduction in luminal FL concentration and demonstrated that intracellular punctate FL accumulation was also markedly reduced. Finally, immunohistochemistry with an anti-tubulin antibody showed that the concentrations of nocodazole used in the above experiments reversibly disrupted microtubules within renal epithelial cells. These data indicate that a component of organic anion secretion in teleost proximal tubule is dependent on an intact microtubular network.
7
Gewin, Leslie S. "Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease." Nutrients 13, no. 5 (May 9, 2021): 1580. http://dx.doi.org/10.3390/nu13051580.
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The kidney is a highly metabolically active organ that relies on specialized epithelial cells comprising the renal tubules to reabsorb most of the filtered water and solutes. Most of this reabsorption is mediated by the proximal tubules, and high amounts of energy are needed to facilitate solute movement. Thus, proximal tubules use fatty acid oxidation, which generates more adenosine triphosphate (ATP) than glucose metabolism, as its preferred metabolic pathway. After kidney injury, metabolism is altered, leading to decreased fatty acid oxidation and increased lactic acid generation. This review discusses how metabolism differs between the proximal and more distal tubular segments of the healthy nephron. In addition, metabolic changes in acute kidney injury and chronic kidney disease are discussed, as well as how these changes in metabolism may impact tubule repair and chronic kidney disease progression.
8
GOBÉ, GLENDA, XIAO-JU ZHANG, DESLEY A. WILLGOSS, ESTELLE SCHOCH, NICOLE A. HOGG, and ZOLTÁN H. ENDRE. "Relationship between Expression of Bcl-2 Genes and Growth Factors in Ischemic Acute Renal Failure in the Rat." Journal of the American Society of Nephrology 11, no. 3 (March 2000): 454–67. http://dx.doi.org/10.1681/asn.v113454.
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Abstract. The promotion of cell survival and regeneration in acute renal failure (ARF) is important for restitution of renal function. This study analyzes the temporal and spatial relationship between expression of pro- and anti-apoptotic members of the Bcl-2 gene family (Bcl-2, Bcl-XL, Bax) and epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and transforming growth factor-β (TGF-β), growth factors that are thought to be reparative in ARF. A rat model of ischemic ARF involving 30 min of bilateral renal artery occlusion followed by reperfusion for 0 to 14 d was used. Apoptosis and mitosis were quantified and qualitative assessment was made of other cellular damage including necrosis and loss of cellular adhesion. Locality and level of expression of the Bcl-2 and growth factor proteins were determined using immunohistochemistry. Apoptosis peaked between 4 and 14 d postischemia in both proximal and distal tubules. Mitosis peaked at 2 d in proximal tubules and 4 to 14 in the distal tubules. A spatio-temporal relationship was observed between anti-apoptotic Bcl-2 gene family members and growth factors after ischemia-reperfusion. In control kidneys, expression of Bcl-2, Bcl-XL was low in epithelium of distal tubules, Bax had low-to-moderate expression in the proximal tubule and had low expression in the distal tubule, EGF and IGF-1 had low-to-moderate expression in the distal tubule, and TGF-β had low expression in the proximal tubule. In contrast, within 24 h of reperfusion, distal tubules showed a marked increase in expression of Bcl-2 and a moderate increase in Bcl-XL and Bax. Proximal tubules showed a marked increase in Bax expression and a moderate increase in Bcl-XL. Twenty-four hours after expression of the Bcl-2 proteins was increased, IGF-1 and EGF protein levels were increased in the distal tubule, similar to the Bcl-2 anti-apoptotic proteins, and were also detected in the adjacent proximal tubules, suggestive of paracrine action in these tubules. TGF-β expression was moderately increased in regenerating proximal tubules, but no relationship was seen with the pattern of expression of the Bcl-2 genes. An explanation of these results is that the distal tubule is adaptively resistant to ischemic injury via promotion of survival by anti-apoptotic Bcl-2 genes, and its survival allows expression of growth factors critical not only to the maintenance and regeneration of its own cell population (autocrine action), but also to the adjacent ischemia-sensitive proximal tubular cells (paracrine action).
9
Shah, Mehul, Raymond Quigley, and Michel Baum. "Maturation of rabbit proximal straight tubule chloride/base exchange." American Journal of Physiology-Renal Physiology 274, no. 5 (May 1, 1998): F883—F888. http://dx.doi.org/10.1152/ajprenal.1998.274.5.f883.
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The present in vitro microperfusion study compared the mechanism and rates of NaCl transport in neonatal and adult rabbit proximal straight tubules. In proximal straight tubules perfused with a late proximal tubular fluid and bathed in a serumlike albumin solution, the rate of volume absorption ( J V) was 0.54 ± 0.10 and 0.12 ± 0.05 nl ⋅ mm−1 ⋅ min−1in adults and neonates, respectively ( P < 0.05). With the addition of 10−5 M bath ouabain, J Vdecreased to 0.27 ± 0.07 and −0.03 ± 0.04 nl ⋅ mm−1 ⋅ min−1in adult and neonatal tubules, respectively ( P < 0.05), consistent with lower rates of active and passive NaCl transport in the neonatal proximal straight tubule. The effect of luminal sodium and chloride removal on intracellular pH was used to assess the relative rates of Na+/H+and Cl−/base exchange. The rates of Na+/H+and Cl−/base exchange were approximately fivefold less in neonatal proximal straight tubules than adult tubules. In both neonatal and adult proximal straight tubules, the rate of Cl−/base exchange was not affected by formate, bicarbonate, or cyanide and acetazolamide, consistent with Cl−/OH−exchange. These data demonstrate an increase in proximal straight tubule NaCl transport during postnatal renal development.
10
Tripathi, S., E. L. Boulpaep, and A. B. Maunsbach. "Isolated perfused Ambystoma proximal tubule: hydrodynamics modulates ultrastructure." American Journal of Physiology-Renal Physiology 252, no. 6 (June 1, 1987): F1129—F1147. http://dx.doi.org/10.1152/ajprenal.1987.252.6.f1129.
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A method using a pressure-sensing servo-pipette is described for measuring downstream transepithelial pressure within isolated renal tubules perfused at flow rates designed to keep luminal solution composition constant. The hydrodynamics of in vitro microperfusion of isolated proximal tubules of Ambystoma tigrinum was varied and different states of transepithelial hydrostatic pressure difference, axial tubule flow, and transepithelial transport were correlated with epithelial ultrastructure. Tubules analyzed by ultrastructural morphometry were as follows: unperfused with and without ouabain, perfused single-end cannulated with and without ouabain, and perfused double-end cannulated tubules incubated in substrate Ringer. The results indicate that proximal tubule fine structure is well preserved for more than 3 h in unperfused and perfused tubules. Small transepithelial hydrostatic pressure gradients (less than 162 Pa) increase tubule diameters and decrease cell height without changing volumes of the cells, lateral intercellular spaces (LIS), or the basal extracellular labyrinth (BEL). Pressure gradients of 271 Pa have no further effect on tubule diameters or cell height, but significantly reduce volumes of LIS and BEL. Transport inhibition and axial flow changes have minor structural effects. This study demonstrates a close dependence of tubule ultrastructure on hydrodynamic conditions and provides guidelines for optimizing the latter during perfusion of isolated renal tubules.
11
Syal, Ashu, Susan Schiavi, Sumana Chakravarty, Vangipuram Dwarakanath, Raymond Quigley, and Michel Baum. "Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro." American Journal of Physiology-Renal Physiology 290, no. 2 (February 2006): F450—F455. http://dx.doi.org/10.1152/ajprenal.00234.2005.
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Fibroblast growth factor-23 (FGF-23) has been implicated in the renal phosphate wasting in X-linked hypophosphatemia, tumor-induced osteomalacia, and autosomal dominant hypophosphatemic rickets. Recently, we demonstrated that Hyp mice have greater urinary PGE2 levels compared with C57/B6 mice and that indomethacin administration in vivo and in vitro ameliorates the phosphate transport defect in Hyp mice. To determine further whether altered prostaglandin metabolism plays a role in the renal phosphate transport defect in Hyp mice, we incubated renal proximal tubules with arachidonic acid. We find that PGE2 production was higher in Hyp mice than in C57/B6 mice. Incubation of C57/B6 mouse renal proximal tubules with FGF-23R176Q, an active mutant form of FGR23, increased tubular PGE2 production, an effect that was inhibited by 50 μM PD-98059 and 10 μM SB-203580, inhibitors of the MAP kinase pathway. C57/B6 mice injected with FGF-23R176Q had a ∼10-fold increase in PGE2 excretion 24 h after intraperitoneal injection of FGF-23R176Q compared with vehicle-treated controls. Finally, we show that PGE2 inhibited both phosphate and volume absorption in mouse proximal convoluted tubules perfused in vitro and reduced brush-border membrane vesicle NaPi-2a protein abundance from renal cortex incubated in vitro with PGE2. In conclusion, FGF-23 increases urinary and renal tubular PGE2 production via the MAP kinase pathway and PGE2 inhibits proximal tubule phosphate transport.
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Wen, Donghai, Li Ni, Li You, Liying Zhang, Yong Gu, Chuan-Ming Hao, and Jing Chen. "Upregulation of nestin in proximal tubules may participate in cell migration during renal repair." American Journal of Physiology-Renal Physiology 303, no. 11 (December 1, 2012): F1534—F1544. http://dx.doi.org/10.1152/ajprenal.00083.2012.
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The characteristics of renal tubular progenitor/precursor cells and the role of renal tubule regeneration in the repair of remnant kidneys (RKs) after nephrectomy are not well known. In the present study of a murine model of subtotal nephrectomy, we used immunofluorescence (IF), immunoblot analysis, and in situ hybridization methods to demonstrate that nestin expression was transiently upregulated in tubule cells near the incision edges of RKs. The nestin-positive tubules were immature proximal tubules that colabeled with lotus tetragonolobus agglutinin but not with markers of mature tubules (aquaporin-1, Tamm-Horsfall protein, and aquaporin-2). In addition, many of the nestin-expressing tubule cells were actively proliferative cells, as indicated by colabeling with bromodeoxyuridine. Double-label IF and immunoblot analysis also showed that the upregulation of tubular nestin was associated with enhanced transforming growth factor-β1 (TGF-β1) expression in the incision edge of RKs but not α-smooth muscle actin, which is a marker of fibrosis. In cultured human kidney proximal tubule cells (HKC), immunoblot analysis indicated that TGF-β1 induced nestin expression and loss of E-cadherin expression, suggesting an association of nestin expression and cellular dedifferentiation. Knockdown of nestin expression by a short hairpin RNA-containing plasmid led to decreased migration of HKC cells that were induced by TGF-β1. Taken together, our results suggest that the tubule repair that occurs during the recovery process following nephrectomy may involve TGF-β1-induced nestin expression in immature renal proximal tubule cells and the promotion of renal cell migration.
13
Li, Huiping, Xiyou Zhou, Deborah R. Davis, Di Xu, and Curt D. Sigmund. "An androgen-inducible proximal tubule-specific Cre recombinase transgenic model." American Journal of Physiology-Renal Physiology 294, no. 6 (June 2008): F1481—F1486. http://dx.doi.org/10.1152/ajprenal.00064.2008.
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To facilitate the study of renal proximal tubules, we generated a transgenic mouse strain expressing an improved Cre recombinase (iCre) under the control of the kidney androgen-regulated protein (KAP) promoter. The transgene was expressed in the kidney of male mice but not in female mice. Treatment of female transgenic mice with androgen induced robust expression of the transgene in the kidney. We confirmed the presence of Cre recombinase activity and the cell specificity by breeding the KAP2-iCRE mice with ROSA26 reporter mice. X-Gal staining of kidney sections from male double transgenic mice showed robust staining in the epithelial cells of renal proximal tubules. β-Gal staining in female mice became evident in proximal tubules after administration of androgen. This model of inducible Cre recombinase in the renal proximal tubule should provide a novel useful tool for studying the physiological significance of genes expressed in the renal proximal tubule. This has advantages over other current models where Cre recombinase expression is constitutive, not inducible.
14
Cui, S., P. J. Verroust, S. K. Moestrup, and E. I. Christensen. "Megalin/gp330 mediates uptake of albumin in renal proximal tubule." American Journal of Physiology-Renal Physiology 271, no. 4 (October 1, 1996): F900—F907. http://dx.doi.org/10.1152/ajprenal.1996.271.4.f900.
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Serum albumin filtered in renal glomeruli is reabsorbed very efficiently in the proximal tubule by endocytosis. The present study was undertaken to determine whether megalin/gp330 binds and mediates endocytosis of albumin. Rat serum albumin (RSA) labeled with 125I and colloidal gold particles labeled with bovine serum albumin (BSA) were microinfused into rat surface proximal tubules in vivo, and tubular uptake was determined in the presence or absence of different substances known to interfere with ligand binding to megalin. Binding of 125I-BSA and 125I-RSA to purified megalin was also determined directly using Sepharose columns. The results revealed that the tubular uptake of 125I-labeled RSA was significantly inhibited by receptor-associated protein (RAP), which reduced the uptake by > 50% and by cold RSA. The uptake of BSA gold by the proximal tubule was very intensive. BSA gold was found in small and large endocytic vacuoles, dense apical tubules, and in lysosomes. The uptake was reduced by RAP to 17%, by EDTA to 19%, by BSA to 16%, by megalin to 35%, by cytochrome c to 49%, and, together with gentamicin, there was virtually no uptake. Megalin-Sepharose columns bound 125I-labeled BSA as well as 125I-RSA, the binding was inhibited by RAP and EDTA, and analysis of the eluate revealed the bound tracer to be albumin. In conclusion, the present study demonstrates that megalin is a mediator of albumin reabsorption in renal proximal tubules.
15
Beyenbach, K. W., and E. Fromter. "Electrophysiological evidence for Cl secretion in shark renal proximal tubules." American Journal of Physiology-Renal Physiology 248, no. 2 (February 1, 1985): F282—F295. http://dx.doi.org/10.1152/ajprenal.1985.248.2.f282.
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The electrophysiology of shark proximal tubules (Squalus acanthias) was investigated using conventional microelectrodes and cable analysis. Under in vitro perfusion with symmetrical Ringer solutions, tubule transepithelial resistance was 36.3 +/- 2.3 omega X cm2 (means +/- SE, n = 44). Other electrophysiological variables varied widely under control conditions. In unstimulated tubules (n = 16) the transepithelial voltage (VT,o) was lumen positive (1.2 +/- 0.2 mV), the basolateral membrane potential (Vbl,x) was -61.3 +/- 1.6 mV, and the fractional resistance of the apical membrane (fRa) was 0.67 +/- 0.02. Spontaneously stimulated tubules (n = 28) had lumen-negative VT,o values (-1.5 +/- 0.4 mV), low Vbl,x values (-41.3 +/- 1.7 mV), and low fRa values (0.30 +/- 0.02). The stimulated state can be induced in unstimulated tubules via treatment with cAMP. Multiple microelectrode impalements in a single tubule revealed epithelial cells sharing similar electrophysiological properties. Selective ion substitutions in the tubule lumen and peritubular bath uncovered an increased Cl conductance in the apical membrane of spontaneously and cAMP-stimulated tubules. Anthracene-9-carboxylic acid tended to reverse the stimulated state, and furosemide hyperpolarized Vbl,x. These results constitute the first evidence for secretory Cl transport in a renal proximal tubule. The electrophysiological responses to ion substitutions, stimulators, and inhibitors are strikingly similar to those of known Cl-transporting epithelia.
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Zager, Richard A., Ali C. M. Johnson, Steven Lund, and Julie Randolph-Habecker. "Toll-like receptor (TLR4) shedding and depletion: acute proximal tubular cell responses to hypoxic and toxic injury." American Journal of Physiology-Renal Physiology 292, no. 1 (January 2007): F304—F312. http://dx.doi.org/10.1152/ajprenal.00237.2006.
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Acute renal failure (ARF) induces tubular hyperresponsiveness to TLR4 ligands, culminating in exaggerated renal cytokine/chemokine production. However, the fate of TLR4 protein during acute tubular injury remains unknown. The study sought new insights into this issue. Male CD-1 mice were subjected to 1) unilateral ischemia-reperfusion (I/R), 2) cisplatin (CP) nephrotoxicity, or 3) glycerol-induced myohemoglobinuric ARF. Renal cortical TLR4 protein (Western blotting, immunohistochemistry) and TLR4 mRNA levels (RT-PCR) were determined thereafter (90 min-4 days). Urinary TLR4 excretion post-I/R or CP injection was also assessed. To gain proximal tubule-specific results, TLR4 protein and mRNA were quantified in posthypoxic or oxidant (Fe)-challenged isolated mouse tubules. Finally, TLR4 mRNA was determined in antimycin A-injured cultured proximal tubular (HK-2) cells. Acute in vivo renal injury reduced proximal tubule TLR4 content. These changes corresponded with the appearance of TLR4 fragment(s) in urine and a persistent increase in renal cortical TLR4 mRNA. Isolated proximal tubules responded to injury with rapid TLR4 reductions, dramatic extracellular TLR4 release, and increases in TLR4 mRNA. Glycine blocked these processes, implying membrane pore formation was involved. HK-2 cell injury increased TLR4 mRNA, but not protein levels, suggesting intact transcriptional, but not translational, pathways. Diverse forms of acute tubular injury rapidly reduce proximal tubular TLR4 content. Plasma membrane TLR4 release through glycine-suppressible pores, possibly coupled with a translation block, appears to be involved. Rapid postinjury urinary TLR4 excretion suggests its potential utility as a “biomarker” of impending ARF.
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Tang, M. J., and R. L. Tannen. "Metabolic substrates alter attachment and differentiated functions of proximal tubule cell culture." Journal of the American Society of Nephrology 4, no. 11 (May 1994): 1908–11. http://dx.doi.org/10.1681/asn.v4111908.
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Proximal tubules cultured in vitro gradually lose their differentiated functions. Because standard culture media lacks several substrates important for renal proximal tubule oxidative metabolism, whether a mixture of substrates including butyrate, alanine, and lactate (BAL) would modify growth and/or differentiated function of proximal tubular cells in culture was examined. Tubules cultured in media supplemented with 2 mM butyrate, alanine, and lactate exhibited enhanced attachment but did not exhibit an altered growth rate. Higher levels of phosphoenolpyruvate carboxykinase and leucine-amino peptidase were sustained, although these activities were still diminished in comparison with that in fresh tubules. Sodium-dependent glucose uptake and dome formation--other reflections of epithelial cell differentiated function--also were enhanced. These studies demonstrate that the substrates used to culture proximal tubules can modify both their attachment and their manifestation of differentiated function in culture.
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Harris, P. J., M. E. Cooper, S. Hiranyachattada, J. L. Berka, D. J. Kelly, M. Nobes, and P. J. Wookey. "Amylin stimulates proximal tubular sodium transport and cell proliferation in the rat kidney." American Journal of Physiology-Renal Physiology 272, no. 1 (January 1, 1997): F13—F21. http://dx.doi.org/10.1152/ajprenal.1997.272.1.f13.
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In autoradiographic studies in anesthetized rats, 125I-labeled amylin binding was associated with proximal convoluted tubules but not distal tubules, interstitium, or glomeruli in the renal cortex. Split-drop micropuncture experiments showed that perfusion of the peritubular capillaries with amylin (10(-9) M) stimulated proximal tubular fluid absorption by 28%. This effect was inhibited by luminal addition of ethylisopropylamiloride, indicating mediation by a brush-border Na+/H+ exchanger. Intravenous infusion of an amylin binding antagonist, AC-187, reduced proximal fluid reabsorption (22%) in anesthetized rats, indicating a role for endogenous amylin in salt homeostasis. In primary cultures of rat proximal tubule cells, amylin (10(-7) M) stimulated proliferation with a potency equal to epidermal growth factor. Peptide antagonists (AC-187, AC-413, and AC-512) of the amylin binding sites in the renal cortex blocked the mitogenic action of amylin. We conclude that amylin acts on renal proximal tubules to promote sodium and water reabsorption and cell proliferation. These novel actions may have implications for the development of hypertension for example in non-insulin-dependent diabetes mellitus and obesity in which hyperamylinemia has been observed.
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Cessac-Guillemet, A. L., F. Mounier, C. Borot, H. Bakala, M. Perichon, M. Schaeverbeke, and J. Schaeverbeke. "Characterization and distribution of albumin binding protein in normal rat kidney." American Journal of Physiology-Renal Physiology 271, no. 1 (July 1, 1996): F101—F107. http://dx.doi.org/10.1152/ajprenal.1996.271.1.f101.
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The mechanism by which proteins that pass through the glomerular basal lamina are taken up by proximal tubule cells is incompletely characterized. Past work has identified the kinetics of albumin binding to renal brush-border membrane. We have now purified and characterized albumin binding protein (ABP) and shown its distribution in renal proximal tubular cells. ABP was purified from rat renal proximal tubular cell brush-border membrane by affinity chromatography with rat serum albumin-Sepharose. The resulting ABP had two apparent molecular masses (55 and 31 kDa) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Antibodies to ABP were raised in rabbits and checked by immunoassay and immunoblotting. Light-microscopic immunohistochemistry showed ABP all along the proximal tubule in the pars convoluta and pars recta. Electron-microscopic immunohistochemistry showed labeling on microvilli and in apical endocytic vacuoles, dense apical tubules, and lysosomes. These results indicate that ABP is involved in proximal tubule endocytosis.
20
Tank, Julia E., William L. Henrich, and Orson W. Moe. "Regulation of glomerular and proximal tubule renin mRNA by chronic changes in dietary NaCl." American Journal of Physiology-Renal Physiology 273, no. 6 (December 1, 1997): F892—F898. http://dx.doi.org/10.1152/ajprenal.1997.273.6.f892.
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Renal adaptations to chronic changes in dietary NaCl and extracellular fluid volume involve both glomerular and tubular mechanisms that result in preservation of glomerular filtration rate and modifications of renal tubular transport to secure external NaCl balance. Although the systemic renin-angiotensin system (RAS) mediates some of these responses, the possible contributions of local glomerular and proximal tubule RASs in these adaptations have not been examined. Thus, in this study, glomeruli and proximal tubules were microdissected from rats adapted to high (4.0%)-, normal (0.5%), or low (0.01%)-NaCl diets, and renin mRNA was measured using quantitative competitive reverse transcription-polymerase chain reaction. After 4 days of the diets, glomerular renin mRNA abundance was increased 100% by the low-NaCl diet ( P < 0.05) and suppressed 50% ( P < 0.01) by the high-NaCl diet compared with controls. Renin mRNA in proximal tubules was stimulated 230% ( P < 0.05) by the low-NaCl diet and tended to be suppressed (68% decrease, not significant) by the high-NaCl diet. When the high-NaCl diet was continued for 2 wk, proximal tubule renin mRNA was suppressed by 89% ( P < 0.05). This study provides evidence that glomerular and proximal tubule renin transcript levels are regulated by chronic changes in dietary NaCl, suggesting that local RASs contribute to the renal adaptations in response to chronic alterations in NaCl.
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Carone, F. A., E. I. Christensen, and G. Flouret. "Degradation and transport of AVP by proximal tubule." American Journal of Physiology-Renal Physiology 253, no. 6 (December 1, 1987): F1120—F1128. http://dx.doi.org/10.1152/ajprenal.1987.253.6.f1120.
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High-performance liquid chromatography (HPLC) analysis revealed that [3,4,5-3H-Phe3,Arg8]vasopressin ([3H]AVP) was not degraded by isolated renal brush-border membranes or by a cortical lysosomal fraction in vitro; however, in the presence of 1 mM reduced glutathione, [3H]AVP was degraded by both preparations. Renal cortical homogenates in vitro and luminal peptidases of proximal tubule in vivo degraded [3H]AVP and in both instances yielded phenylalanine, hexapeptide AVP 1-6, heptapeptide AVP 1-7, octapeptide AVP 1-8, and two uncharacterized products X and Y. These data suggest that filtered AVP is reduced in the proximal tubule by a reduced glutathione-dependent transhydrogenase and subsequently cleaved to [3H]Phe by tubular aminopeptidases. Following microinfusion of [3H]AVP into proximal tubules, 15.7% of the label was absorbed. Five and fifteen minutes after infusion of [3H]AVP, sequestration of total label in proximal tubules was 4.5 and 2.1%, respectively, and quantitative electron microscope autoradiography revealed accumulation of grains over apical endocytic vacuoles and lysosomes consistent with endocytic uptake and rapid lysosomal degradation of AVP and/or a large metabolite. Thus, enzymatic cleavage of AVP by luminal and lysosomal peptidases in proximal tubules could involve disulfide bond, C-terminal, and N-terminal loci.
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Cliff, W. H., and K. W. Beyenbach. "Fluid secretion in glomerular renal proximal tubules of freshwater-adapted fish." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 254, no. 1 (January 1, 1988): R154—R158. http://dx.doi.org/10.1152/ajpregu.1988.254.1.r154.
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Tubular secretion by renal proximal tubules, as a mechanism for delivering fluid and electrolytes to the urine, has received little attention in modern conceptions of renal function in vertebrates even though it is the mechanism for urine production in aglomerular fish. This report demonstrates that some proximal tubules of glomerular kidneys of freshwater-adapted euryhaline fish spontaneously secrete fluid. The fluid consists primarily of Na (138 mM) and Cl (160 mM). NaCl and fluid secretion can be stimulated by adenosine 3',5-cyclic monophosphate, suggesting that tubular fluid secretion is under hormonal control. Fluid secretion driven by NaCl secretion in glomerular proximal tubules of fish that already filter NaCl and water suggests that secretion of fluid and NaCl may play a fundamental role in vertebrate renal function beyond a preadaptation for aglomerular urine formation.
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Abuazza, Ghazala, Amy Becker, Scott S. Williams, Sumana Chakravarty, Hoang-Trang Truong, Fangming Lin, and Michel Baum. "Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins." American Journal of Physiology-Renal Physiology 291, no. 6 (December 2006): F1132—F1141. http://dx.doi.org/10.1152/ajprenal.00063.2006.
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The adult proximal tubule is a low-resistance epithelium where there are high rates of both active transcellular and passive paracellular NaCl transport. We have previously demonstrated that the neonatal rabbit and rat proximal tubule have substantively different passive paracellular transport properties than the adult proximal tubule, which results in a maturational change in the paracellular passive flux of ions. Neonatal proximal tubules have a higher PNa/PCl ratio and lower chloride and bicarbonate permeabilities than adult proximal tubules. Claudins are a large family of proteins which are the gate keepers of the paracellular pathway, and claudin isoform expression determines the permeability characteristics of the paracellular pathway. Previous studies have shown that claudins 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 15, and 16 are expressed in the adult mouse kidney. To determine whether there are developmental claudin isoforms, we compared the claudin isoforms present in the neonatal and adult kidney using RT-PCR to detect mRNA of claudin isoforms. Claudin 6, claudin 9, and claudin 13 were either not expressed or barely detectable in the adult mouse kidney using traditional PCR, but were expressed in the neonatal mouse kidney. Using real-time RT-PCR, we were able to detect a low level of claudin 6 mRNA expression in the adult kidney compared with the neonate, but claudin 9 and claudin 13 were only detected in the neonatal kidney. There was the same maturational decrease in these claudin proteins with Western blot analysis. Immunohistochemistry showed high levels of expression of claudin 6 in neonatal proximal tubules, thick ascending limb, distal convoluted tubules, and collecting ducts in a paracellular distribution but there was no expression of claudin 6 in the adult kidney. Using real-time RT-PCR claudin 6 and 9 mRNA were present in 1-day-old proximal convoluted tubules and were virtually undetectable in proximal convoluted tubules from adults. Claudin 13 was not detectable in neonatal or adult proximal convoluted tubules. In summary, we have identified developmentally expressed claudin isoforms, claudin 6, claudin 9, and claudin 13. These paracellular proteins may play a role in the maturational changes in paracellular permeability.
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VOGEL, MORITZ, BETTINA KRÄNZLIN, JÖRG BIBER, HEINI MURER, NORBERT GRETZ, and SEBASTIAN BACHMANN. "Altered Expression of Type II Sodium/Phosphate Contransporter in Polycystic Kidney Disease." Journal of the American Society of Nephrology 11, no. 10 (October 2000): 1926–32. http://dx.doi.org/10.1681/asn.v11101926.
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Abstract. Renal phosphate (Pi) absorption is mediated via the type II sodium/Pi cotransporter (NaPi-2) in the brush border membrane (BBM) of proximal tubules. Simultaneous detection of NaPi-2 mRNA by in situ hybridization and of NaPi-2 immunoreactivity by immunohistochemistry was performed to investigate the distribution of the cotransporter in healthy control rats and during progression of autosomal dominant polycystic kidney disease (ADPKD). The purpose of the study was to disclose a relation between proximal tubular cell differentiation and NaPi-2 expression. In controls, NaPi-2 expression was present in the entire proximal tubule. In the Han:SPRD (cy/+) model for ADPKD, the proximal nephron is primarily affected by the cystic changes. Epithelial proliferation and impaired epithelial-matrix interaction result in a loss of cell differentiation that eventually leads to cystic enlargement of the nephron. Normal expression of NaPi-2 in this model was found only in tubules with intact BBM. Loss of BBM and cellular interdigitation were paralleled by the loss of NaPi-2 in situ hybridization and immunoreactive signals. These changes were moderate and focal in 2-mo-old rats and generalized all over the cortex after 8 mo. Advanced renal damage in the older PKD group was associated with mild phosphaturia, which suggests functional insufficiency of tubular NaPi-2 reabsorption. These data show how proliferative changes and loss of tubular epithelial differentiation in ADPKD may prevent functional expression of the NaPi-2 system in the proximal tubule in a rapidly progressive manner. NaPi-2 in proximal tubule BBM is suggested to play an important role in impaired tubular absorption of Pi in renal disease.
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M, Lubis, Alvarino Alvarino, Tofrizal Tofrizal, and Erkadius Erkadius. "Pengaruh Pemberian Valsartan Dan Kurkumin Terhadap Pembentukan Fibrosis Di Tubulus Proksimal Ginjal Akibat Obstruksi Ureter Unilateral pada Tikus Wistar." Jurnal Kesehatan Andalas 2, no. 1 (January 1, 2013): 01. http://dx.doi.org/10.25077/jka.v2i1.53.
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AbstrakPendahuluan: Obstruksi ureter adalah kondisi terhalangnya aliran urin dari ginjal ke buli-buli, adanya obstruksi pada ureter memperlambat laju filtrasi glomerulus dan dapat menyebabkan kerusakan parenkim ginjal. Fibrosis pada ginjal yang obstruksi timbul melalui dua mediator yaitu tumor nekrotik factor (TNF-α) dan angiotensin II. Penghambatan kedua mediator ini akan menurunkan tingkat fibrosis di tubulus proksimal ginjal akibat obstruksi. Zat yang bisa menghambat TNF-α salah satunya adalah kurkumin sedangkan Angitensin II dapat dihambat dengan valsatran. Metode: Penelitian ini merupakan penelitian eksperimental, tikus wistar dibagi dalam dua kelompok dengan jumlah tiap kelompok adalah 15 ekor. Proksimal ureter kanan diikat dan kelompok perlakuan 1 sebagai kontrol diberi valsatran, kelompok perlakuan2 diberi valsartan dan kurkumin. Pemberian oral, dimana obat dilakukan pengenceran. Hari ke lima belas dilakukan pengambilan ginjal tikus wistar, diperiksa histologi. Pembentukan fibrosis di tubulus proksimal dianalisa dengan uji statistik chisquare dengan koreksi Yates dan t test, sedang terbentuknya degenerasi hidrofik dan terbentuknya atrofi pada tubulus proksimal dianalisa dengan uji statistik t test. Hasil: Adanya perbedaan bermakna perubahan pembentukan fibrosis di tubulus proksimal ginjal antara kelompok perlakuan dan kontrol ( Chi Squqre didapat nilai p ≤ 0,001 dan dengan t test didapat nilai p ≤ 0,000). Terbentuknya degenerasi hidrofilik di tubulus proksimal ginjal terdapat perbedaan bermakna terbentuknya degenerasi hidrofilik kelompok perlakuan dan kelompok kontrol ( t test didapatkan nilai p ≤ 0,000). Terbentuknya atrofi di tubulus proksimal terdapatt perbedaan bermakna terbentuknya atrofi di tubulus proksimal ginjal kelompok perlakuan dan kelompok kontrol ( t test didapat nilai p ≤ 0,000). Kesimpulan: Ada perbedaan pengaruh pemberian valsartan dan valsartan + kurkumin terhadap pembentukan fibrosis di tubulus proksimal ginjal. Perbedaan bermakna terbentuKata kunci: Obstruksi ureter, Valsartan, Kurkumin, Fibrosis, Degenerasi hidrofilik, AtrofiAbstractIntroduction: ureter obstruction is a condition where is an obstacle for urine flow from renal to blast (vesica urinaria). The obstruction in ureter will decrease glomerulus filtration flow and it destroys renal parenchym. Fibroses in obstructed renal present through two mediators, there are necrotizing tumor factors-α (TNF-α) and angiotension-II. Obstruction of this two mediators will decrease fibroses grading in proximal tubules of renal caused by obtruction. One of TNF-α inhibitors is curcumene and angiotension-II will be obstructed by valsartan. Methods: this experiment is kind of experimental type using animal experiment (Wistar Mice). Wistar Mice are divided into two groups, each group consist of 15 mice, so the total are 30 mice. This animals tighted with at proximal ureter The first group is control one, given valsartan. The second group is given valsartan and curcumene. Oral route and dilution before given. Medicine is given use 1 cc spuit. Giving action in 14 days. The fifteenth day, we take renal of Wistar and do histology examination. Significant difference between fibroses forming in proximal tubulus analyzed by Chi Square Statistic Test with correction of Yates and T-Test, beside that, hydofic degeneration and atrophy in proximal tubulus analyzed by T-Test Statistic Test. Result: there is significant difference in forming of fibroses in proximal tubules of renal between action group and controlled group (Chi Square with p ≤ 0.0001 and T-Test with p ≤ 0.000). In hydrophilic degeneration forming in proximal tubules gotten significant difference between two groups ( T-Test with p ≤ 0.000). In atrophy forming in proximal tubules, there is important difference between two groups (T-Test with p ≤ 0.000).Concultion. There is an effect in giving valsartan and curcumene to fibroses forming in proximal tubules of renal. There is significant difference in hydrophilic degeneration in proximal tubules of renal. And also there is important difference in atrophy forming in proximal tubules between two groups.Keywords:ureter obstruction, valsartan, curcumene, fibroses, hydrophilic degeneration, atrophy.
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De Paepe, Monique E., Emily Stopa, Carol Huang, Katrine Hansen, and Francois I. Luks. "Renal Tubular Apoptosis in Twin-to-Twin Transfusion Syndrome." Pediatric and Developmental Pathology 6, no. 3 (May 2003): 215–25. http://dx.doi.org/10.1177/109352660300600301.
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Twin-to-twin transfusion syndrome (TTTS) is caused by uneven shunting of blood between monochorionic twins, resulting in polycythemia in the recipient twin and growth restriction, anemia, and oliguria in the donor twin. Recent reports have described loss of proximal convoluted tubules in the kidneys of TTTS donor twins. In order to elucidate the pathogenesis of tubular deficiency in TTTS, we have reviewed the renal pathology in 25 twin pairs with autopsy-proven TTTS. Loss of differentiated proximal tubules, associated with atrophy of medullary tubules, was identified in 12/25 donor twins. In seven of these cases (all > 23-wk gestational age), the kidneys showed diffuse or partial tubular atrophy without evidence of cell death, similar to previously reported patterns. In five cases (all between 18- and 22-wk gestation), proximal and medullary tubules showed active injury characterized by markedly increased apoptosis, cell detachment, and intraluminal cell debris associated with calcifications. Tubular apoptosis tended to be more prevalent in donor fetuses with greater inter-twin body weight discordance, consistent with a more severe degree of TTTS. These results extend the spectrum of tubular alterations in TTTS to include an early stage of active apoptotic injury. The temporal distribution of injury patterns suggests that apoptotic injury of proximal and medullary tubules may be a precursor to partial or diffuse tubular atrophy. We speculate that the risk for development of tubular apoptosis in TTTS depends on the severity and timing of the hemodynamic imbalance, whereby early mid-trimester fetuses may be more vulnerable.
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Yanagawa, N., and O. D. Jo. "Possible role of calcium in parathyroid hormone actions in rabbit renal proximal tubules." American Journal of Physiology-Renal Physiology 250, no. 5 (May 1, 1986): F942—F948. http://dx.doi.org/10.1152/ajprenal.1986.250.5.f942.
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Using a glucose microassay and in vitro isolated renal tubule perfusion technique, we have studied the actions of parathyroid hormone (PTH) on gluconeogenesis (GNG) and fluid (Jv) and phosphate (Jp) transport rates in isolated rabbit renal proximal tubules. In proximal straight tubules (PST), PTH stimulated GNG and inhibited Jv and Jp. In proximal convoluted tubules (PCT), PTH inhibited Jv but failed to affect GNG and Jp. An increase in Ca concentration, however, stimulated GNG and allowed PTH to inhibit Jp in PCT. Addition of the intracellular Ca antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) abolished the inhibitory effects of PTH on Jv and Jp in both PCT and PST. In conclusion, these studies suggest that Ca-dependent intracellular pathways may be involved in the actions of PTH in rabbit renal proximal tubules. The altered response to PTH in rabbit PCT may be due to alterations in the response of intracellular Ca to the hormone.
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Lee, H. Thomas, Michael Jan, Soo Chan Bae, Jin Deok Joo, Farida R. Goubaeva, Jay Yang, and Mihwa Kim. "A1 adenosine receptor knockout mice are protected against acute radiocontrast nephropathy in vivo." American Journal of Physiology-Renal Physiology 290, no. 6 (June 2006): F1367—F1375. http://dx.doi.org/10.1152/ajprenal.00347.2005.
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The role of renal A1 adenosine receptors (A1AR) in the pathogenesis of radiocontrast nephropathy is controversial. We aimed to further elucidate the role of A1AR in the pathogenesis of radiocontrast nephropathy and determine whether renal proximal tubule A1AR contribute to the radiocontrast nephropathy. To induce radiocontrast nephropathy, A1AR wild-type (WT) or knockout (KO) mice were injected with a nonionic radiocontrast (iohexol, 1.5–3 g iodine/kg). Some A1WT mice were pretreated with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; a selective A1AR antagonist) before iohexol injection. A1AR contribute to the pathogenesis of radiocontrast nephropathy in vivo as the A1WT mice developed significantly worse acute renal failure, more renal cortex vacuolization, and had lower survival 24 h after iohexol treatment compared with the A1KO mice. DPCPX pretreatment also protected the A1WT mice against radiocontrast-induced acute renal failure. No differences in renal cortical apoptosis or inflammation were observed between A1WT and A1KO mice. To determine whether the proximal tubular A1AR mediate the direct renal cytotoxicity of radiocontrast, we treated proximal tubules in culture with iohexol with or without 2-chloro- N6-cyclopentyladenosine (a selective A1AR agonist) or DPCPX pretreatment. We also subjected cultured proximal tubule cells overexpressing A1AR or lacking A1AR to radiocontrast injury. Iohexol caused a direct dose-dependent reduction in proximal tubule cell viability as well as proliferation. Neither the A1AR agonist nor the antagonist treatment affected proximal tubule viability or proliferation. Moreover, overexpression or lack of A1AR failed to impact the iohexol toxicity on proximal tubule cells. Therefore, we conclude that radiocontrast causes acute renal failure via mechanisms dependent on A1AR; however, renal proximal tubule A1AR do not contribute to the direct tubular toxicity of radiocontrast.
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Goralski, Kerry B., Dwayne G. Stupack, Grant M. Hatch, and Daniel S. Sitar. "Perturbation of rat renal tubule transport of the organic cation amantadine in recent onset streptozotocin-induced diabetes and in uninephrectomy." Canadian Journal of Physiology and Pharmacology 79, no. 1 (January 1, 2001): 18–24. http://dx.doi.org/10.1139/y00-104.
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The effects of early-stage diabetes mellitus and uninephrectomy on the renal tubule transport of amantadine were investigated. Kidney tubules were isolated from streptozotocin-induced diabetic (± insulin treatment), uninephrectomized, and control male Sprague-Dawley rats. There were no differences in the Km of amantadine uptake in renal proximal and distal tubules for the imposed treatments compared with control values. Vmax for amantadine uptake in the proximal tubules of diabetic and uninephrectomized rats was higher than the respective control (P < 0.05). Vmax for insulin-treated diabetic rats was similar to control values but was lower than that for untreated diabetic rats (P < 0.05). Vmax for distal tubule uptake was not altered by any treatment. Structure-activity studies demonstrated that bicarbonate-dependent amantadine uptake was inhibited by glycolate and lactate, but not by propionate or α-, β-, or γ-hydroxybutyrate. Early stage streptozotocin-induced diabetes mellitus and uninephrectomy induced changes in the kidney that resulted in a similar selective increase in proximal tubule amantadine uptake. These data represent the first description that experimentally induced diabetes mellitus and uninephrectomy modulate the function of the renal tubule organic cation (amantadine) transport system. Both interventions represent potential models in which phenotypic modulation of the renal elimination of organic cationic drugs may be achieved and studied.Key words: amantadine, organic cation transport, renal tubules, diabetes, uninephrectomy.
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Matsui, Isao, Takayuki Hamano, Satoshi Mikami, Kazunori Inoue, Akihiro Shimomura, Yasuyuki Nagasawa, Toshimi Michigami, et al. "Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats." American Journal of Physiology-Renal Physiology 304, no. 6 (March 15, 2013): F751—F760. http://dx.doi.org/10.1152/ajprenal.00329.2012.
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The serum glycoprotein fetuin-A is an important inhibitor of extraosseous calcification. The importance of fetuin-A has been confirmed in fetuin-A null mice, which develop widespread extraosseous calcification including the kidney. However, the mechanism how fetuin-A protects kidneys from nephrocalcinosis remains uncertain. Here, we demonstrate that intratubular fetuin-A plays a role in the prevention of nephrocalcinosis in the proximal tubules. Although normal rat kidney did not express mRNA for fetuin-A, we found punctate immunohistochemical staining of fetuin-A mainly in the S1 segment of the proximal tubules. The staining pattern suggested that fetuin-A passed through the slit diaphragm, traveled in the proximal tubular lumen, and was introduced into proximal tubular cells by megalin-mediated endocytosis. To test this hypothesis, we inhibited the function of megalin by intravenous injection of histidine-tagged soluble receptor-associated protein (His-sRAP), a megalin inhibitor. His-sRAP injection diminished fetuin-A staining in the proximal tubules and led to urinary excretion of fetuin-A. We further analyzed the role of fetuin-A in nephrocalcinosis. Continuous injection of parathyroid hormone (PTH) 1–34 induced nephrocalcinosis mainly in the proximal tubules in rats. His-sRAP retained fetuin-A in renal tubular lumen and thereby protected the kidneys of PTH-treated rats from calcification. Our findings suggest that tubular luminal fetuin-A works as a natural inhibitor against calcification in the proximal tubules under PTH-loaded condition.
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Handa, Rajash K., Jack W. Strandhoy, Carlos E. Giammattei, and Shelly E. Handa. "Platelet-activating factor and solute transport processes in the kidney." American Journal of Physiology-Renal Physiology 284, no. 2 (February 1, 2003): F274—F281. http://dx.doi.org/10.1152/ajprenal.00117.2002.
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We examined the hemodynamic and tubular transport mechanisms by which platelet-activating factor (PAF) regulates salt and water excretion. In anesthetized, renally denervated male Wistar rats, with raised systemic blood pressure and renal arterial blood pressure maintained at normal levels, intrarenal PAF infusion at 2.5 ng · min−1 · kg−1resulted in a small fall in systemic blood pressure (no change in renal arterial blood pressure) and an increase in renal blood flow and urinary water, sodium, and potassium excretion rates. The PAF-induced changes in cardiovascular and renal hemodynamic function were abolished and renal excretory function greatly attenuated by treating rats with a nitric oxide synthase inhibitor. To determine whether a tubular site of action was involved in the natriuretic effect of PAF, cortical proximal tubules were enzymatically dissociated from male Wistar rat kidneys, and oxygen consumption rates (Qo 2) were used as an integrated index of transcellular sodium transport. PAF at 1 nM maximally inhibited Qo 2 in both untreated and nystatin-stimulated (sodium entry into renal cell is not rate limiting) proximal tubules by ∼20%. Blockade of PAF receptors or Na+-K+-ATPase pump activity with BN-52021 or ouabain, respectively, abolished the effect of PAF on nystatin-stimulated proximal tubule Qo 2. Inhibition of nitric oxide synthase or guanylate cyclase systems did not alter PAF-mediated inhibition of nystatin-stimulated proximal tubule Qo 2, whereas phospholipase A2 or cytochrome- P-450 monooxygenase inhibition resulted in a 40–60% reduction. These findings suggest that stimulation of PAF receptors on the proximal tubule decreases transcellular sodium transport by activating phospholipase A2 and the cytochrome- P-450 monooxygenase pathways that lead to the inhibition of an ouabain-sensitive component of the basolateral Na+-K+-ATPase pump. Thus PAF can activate both an arachidonate pathway-mediated suppression of proximal tubule sodium transport and a nitric oxide pathway-mediated dilatory action on renal hemodynamics that likely contributes to the natriuresis and diuresis observed in vivo.
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Beyenbach, K. W. "Secretory NaCl and volume flow in renal tubules." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 250, no. 5 (May 1, 1986): R753—R763. http://dx.doi.org/10.1152/ajpregu.1986.250.5.r753.
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This review attempts to give a retrospective survey of the available evidence concerning the secretion of NaCl and fluid in renal tubules of the vertebrate kidney. In the absence of glomerular filtration, epithelial secretory mechanisms, which to this date have not been elucidated, are responsible for the renal excretion of NaCl and water in aglomerular fish. However, proximal tubules isolated from glomerular fish kidneys of the flounder, killifish, and the shark also have the capacity to secrete NaCl and fluid. In shark proximal tubules, fluid secretion appears to be driven via secondary active transport of Cl. In another marine vertebrate, the sea snake, secretion of Na (presumably NaCl) and fluid is observed in freshwater-adapted and water-loaded animals. Proximal tubules of mammals can be made to secrete NaCl in vitro together with secretion of aryl acids. An epithelial cell line derived from dog kidney exhibits secondary active secretion of Cl when stimulated with catecholamines. Tubular secretion of NaCl and fluid may serve a variety of renal functions, all of which are considered here. The occurrence of NaCl and fluid secretion in glomerular proximal tubules of teleosts, elasmobranchs, and reptiles and in mammalian renal tissue cultures suggests that the genetic potential for NaCl secretion is present in every vertebrate kidney.
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Pereira-Moreira, Ricardo, and Elza Muscelli. "Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review." Journal of Diabetes Research 2020 (January 10, 2020): 1–17. http://dx.doi.org/10.1155/2020/8492467.
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Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.
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Lewington, Andrew J. P., Babu J. Padanilam, Daniel R. Martin, and Marc R. Hammerman. "Expression of CD44 in kidney after acute ischemic injury in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 278, no. 1 (January 1, 2000): R247—R254. http://dx.doi.org/10.1152/ajpregu.2000.278.1.r247.
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De novo CD44 and ligand expression at wound margins accompanies cellular proliferation and migration that effect repair of injured mucosal and vascular endothelial tissues. To determine whether CD44 could play a role in recovery from acute ischemic renal injury, we characterized its renal expression and those of two of its ligands, hyaluronic acid and osteopontin. Although no expression is detectable in nonischemic kidneys, several mRNAs for CD44 are present within 1 day after injury. CD44 mRNA is expressed in proximal tubules undergoing repair. CD44 peptide is present in basal and lateral cell membranes. Hyaluronic acid is normally expressed in the interstitium of the renal papilla only. By 1 day postischemia, hyaluronic acid can be detected, in addition, in the interstitium surrounding regenerating tubules. Osteopontin, not normally expressed in the renal proximal tubule, is expressed in regenerating tubules by 3 days after induction of acute ischemic injury. Immunoreactive osteopontin peptide continues to be localized in those tubules still undergoing repair for as long as 7 days after the injury. Our data are consistent with a role for CD44-ligand interactions in the regenerating proximal tubule participating in the process of recovery after ischemic injury.
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Cosner, Diane, Xu Zeng, and Ping L. Zhang. "Proximal Tubular Injury in Medullary Rays Is an Early Sign of Acute Tacrolimus Nephrotoxicity." Journal of Transplantation 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/142521.
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Tacrolimus (FK506) is one of the principal immunosuppressive agents used after solid organ transplantations to prevent allograft rejection. Chronic renal injury induced by tacrolimus is characterized by linear fibrosis in the medullary rays; however, the early morphologic findings of acute tacrolimus nephrotoxicity are not well characterized. Kidney injury molecule-1 (KIM-1) is a specific injury biomarker that has been proven to be useful in the diagnosis of mild to severe acute tubular injury on renal biopsies. This study was motivated by a patient with acute kidney injury associated with elevated serum tacrolimus levels in whom KIM-1 staining was present only in proximal tubules located in the medullary rays in the setting of otherwise normal light, immunofluorescent, and electron microscopy. We subsequently evaluated KIM-1 expression in 45 protocol and 39 indicated renal transplant biopsies to determine whether higher serum levels of tacrolimus were associated with acute segment specific injury to the proximal tubule, as reflected by KIM-1 staining in the proximal tubules of the cortical medullary rays. The data suggest that tacrolimus toxicity preferentially affects proximal tubules in medullary rays and that this targeted injury is a precursor lesion for the linear fibrosis seen in chronic tacrolimus toxicity.
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Wright, P. A., and M. A. Knepper. "Phosphate-dependent glutaminase activity in rat renal cortical and medullary tubule segments." American Journal of Physiology-Renal Physiology 259, no. 6 (December 1, 1990): F961—F970. http://dx.doi.org/10.1152/ajprenal.1990.259.6.f961.
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To determine whether local production of ammonium by medullary renal tubule segments may contribute to medullary ammonium accumulation, we measured activities of phosphate-dependent glutaminase (PDG) in microdissected tubule segments from rat medulla and cortex. PDG activities were very low in medullary loop of Henle segments but surprisingly high in inner medullary collecting duct (IMCD). In cortex, PDG levels were highest in distal convoluted tubule and cortical thick ascending limb, but substantial levels were also found in proximal segments, as reported previously. To determine effects of acid loading and alkali loading on PDG activity, 0.28 M NH4Cl (acid) or 0.28 M NaHCO3 (alkali) was added to rats' drinking water for 7 days. PDG activities in medullary segments were not affected by acid or alkali intake. Acid intake by rats increased PDG activity in S1 and S2 proximal convoluted tubules severalfold but did not affect the other cortical segments. We conclude that medullary loop of Henle segments probably contribute relatively little to medullary ammonium accumulation because of their low activities. The high PDG activity in IMCD suggests that ammonium could be produced and secreted by this segment. However, because total tubule length of IMCD is very low compared with proximal tubules, it appears unlikely that IMCD contributes substantially to overall renal ammonium production. PDG activity is regulated only in S1 and S2 proximal tubules, consistent with the view that the proximal tubule is the major site of regulation of renal ammonium production.
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Wilson, Bryan A., Nildris Cruz-Diaz, Yixin Su, James C. Rose, TanYa M. Gwathmey, and Mark C. Chappell. "Angiotensinogen import in isolated proximal tubules: evidence for mitochondrial trafficking and uptake." American Journal of Physiology-Renal Physiology 312, no. 5 (May 1, 2017): F879—F886. http://dx.doi.org/10.1152/ajprenal.00246.2016.
Full textAbstract:
The renal proximal tubules are a key functional component of the kidney and express the angiotensin precursor angiotensinogen; however, it is unclear the extent that tubular angiotensinogen reflects local synthesis or internalization. Therefore, the current study established the extent to which angiotensinogen is internalized by proximal tubules and the intracellular distribution. Proximal tubules were isolated from the kidney cortex of male sheep by enzymatic digestion and a discontinuous Percoll gradient. Tubules were incubated with radiolabeled 125I-angiotensinogen for 2 h at 37°C in serum/phenol-free DMEM/F12 media. Approximately 10% of exogenous 125I-angiotensinogen was internalized by sheep tubules. Subcellular fractionation revealed that 21 ± 4% of the internalized 125I-angiotensinogen associated with the mitochondrial fraction with additional labeling evident in the nucleus (60 ± 7%), endoplasmic reticulum (4 ± 0.5%), and cytosol (15 ± 4%; n = 4). Subsequent studies determined whether mitochondria directly internalized 125I-angiotensinogen using isolated mitochondria from renal cortex and human HK-2 proximal tubule cells. Sheep cortical and HK-2 mitochondria internalized 125I-angiotensinogen at a comparable rate of (33 ± 9 vs. 21 ± 10 pmol·min−1·mg protein−1; n = 3). Lastly, unlabeled angiotensinogen (100 nM) competed for 125I-angiotensinogen uptake to a greater extent than human albumin in HK-2 mitochondria (60 ± 2 vs. 16 ± 13%; P < 0.05, n = 3). Collectively, our data demonstrate angiotensinogen import and subsequent trafficking to the mitochondria in proximal tubules. We conclude that this pathway may constitute a source of the angiotensinogen precursor for the mitochondrial expression of angiotensin peptides.
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Haas, J. A., J. P. Granger, and F. G. Knox. "Effect of intrarenal volume expansion on proximal sodium reabsorption." American Journal of Physiology-Renal Physiology 255, no. 6 (December 1, 1988): F1178—F1182. http://dx.doi.org/10.1152/ajprenal.1988.255.6.f1178.
Full textAbstract:
The objective of the present study was to examine the effect of direct expansion of the renal interstitial volume on sodium reabsorption by proximal tubules of superficial and deep nephrons in the absence of systemic extracellular volume expansion. Renal interstitial volume expansion was achieved by injection of 50 microliter of 2.5% albumin in 0.9% saline into the renal interstitium via a polyethylene matrix that was chronically implanted in the interstitium of the rat kidney. Renal interstitial volume expansion increased renal interstitial hydrostatic pressure from 3.8 +/- 0.5 to 6.8 +/- 1.1 mmHg, P less than 0.05 (n = 5 rats). Fractional reabsorption of sodium by the superficial late proximal tubule decreased from 45.7 +/- 5.6 to 34.2 +/- 5.4%, P less than 0.05, and by the proximal tubule and descending limb of Henle's loop of deep nephrons it decreased from 73.9 +/- 2.9 to 57.2 +/- 6.3%, P less than 0.05 (n = 8 rats). Thus expansion of the renal interstitial volume increased renal interstitial hydrostatic pressure and decreased sodium reabsorption by the proximal tubules of superficial and deep nephrons.
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Dominguez, J. H., K. Camp, L. Maianu, H. Feister, and W. T. Garvey. "Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats." American Journal of Physiology-Renal Physiology 266, no. 2 (February 1, 1994): F283—F290. http://dx.doi.org/10.1152/ajprenal.1994.266.2.f283.
Full textAbstract:
The renal reabsorption of glucose is mediated by two major classes of transporters. Initially, luminal glucose is concentrated in tubules by Na(+)-glucose cotransporters (Na(+)-GLUT). Afterwards, glucose reaches the blood space through facilitative glucose transporters, low-Michaelis constant (Km) GLUT1 and high-Km GLUT2. Hence, the transtubular flux of glucose could be impaired in hyperglycemia because the outwardly directed glucose gradient, from tubule to blood, is potentially lowered. However, in diabetic rats, transtubular glucose flux is not reduced but increased. In this work the molecular mechanism underlying this adaptation was examined. We tested the hypothesis that upregulation of renal tubular high-Km GLUT2 gene may compensate for the decrease in the tubule to blood glucose gradient. In rat tubules, GLUT1 protein and mRNA steady-state levels were reduced, and GLUT2 protein and mRNA levels were increased in rats after 2, 3, and 4 wk of uncontrolled streptozotocin-induced diabetes. These molecular adaptations were associated with augmented facilitative glucose flux. In summary, changes in GLUT1 and GLUT2 gene expression are important to the preservation of renal glucose reabsorption in hyperglycemia.
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Groves, C. E., K. K. Evans, W. H. Dantzler, and S. H. Wright. "Peritubular organic cation transport in isolated rabbit proximal tubules." American Journal of Physiology-Renal Physiology 266, no. 3 (March 1, 1994): F450—F458. http://dx.doi.org/10.1152/ajprenal.1994.266.3.f450.
Full textAbstract:
The physiological characteristics of peritubular organic cation transport were examined by measuring the transport of the organic cation tetraethylammonium (TEA) in rabbit renal proximal tubule suspensions and isolated nonperfused rabbit renal proximal tubules. Peritubular organic cation transport in both single S2 segments and suspensions of isolated renal proximal tubules was found to be a high-capacity, high-affinity, carrier-mediated process. For tubule suspensions, the maximal capacity of the carrier for TEA (Jmax) and the concentration of TEA at 1/2 Jmax (Kt) (1.49 +/- 0.21 nmol.min-1.mg dry wt-1 and 131 +/- 16 microM, respectively), did not differ significantly from those measured in single S2 segments (Jmax, 1.16 +/- 0.075 nmol.min-1.mg dry wt-1; Kt, 108 +/- 10 microM). In addition, the pattern of inhibition of peritubular TEA transport by long-chain n-tetraalkylammonium compounds (n = 1-5) was both qualitatively and quantitatively similar in single S2 segments and tubule suspensions, exhibiting an increase in inhibitory potency with increasing alkyl chain length. For example, in tubule suspensions, apparent Michaelis constants for inhibition of TEA uptake ranged from 1.3 mM for tetramethylammonium (TMA) to 0.8 microM for tetrapentylammonium (TPeA). To determine whether these compounds were substrates for the peritubular organic cation transporter, their effect on the efflux of [14C]TEA from tubule suspensions was examined. A concentration of 0.5 mM of the short-chain tetraalkyls TMA or TEA increased the efflux of [14C]TEA (i.e., trans-stimulated) from tubules in suspension. The longer-chain tetraalkyls tetrapropylammonium, tetrabutylammonium, and TPeA all decreased the efflux of [14C]TEA from tubules in suspension; TPeA completely blocked efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
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Guo, Rong, Li Liu, and Luciano Barajas. "RT-PCR study of the distribution of connexin 43 mRNA in the glomerulus and renal tubular segments." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 275, no. 2 (August 1, 1998): R439—R447. http://dx.doi.org/10.1152/ajpregu.1998.275.2.r439.
Full textAbstract:
An RT-PCR study of the distribution of connexin 43 (Cx43) mRNA in glomeruli and along the rat tubular segments was carried out to establish the differential expression of Cx43 in the different segments of the tubule, in renal regions, in isolated glomerular preparations (IGP), and in microdissected glomeruli. The mRNA level of Cx43 in macrodissected renal regions appeared in the following order: inner papilla > outer papilla and IGP > outer medulla and cortex. Among the microdissected tubules, inner medullary collecting ducts (IMCD) expressed the highest level of Cx43 mRNA, followed by the cortical collecting ducts (CCD). The proximal convoluted tubules and proximal straight tubules expressed significantly less Cx43 than the IMCD, glomeruli, and CCD. Medullary thick ascending limb and distal convoluted tubules showed the lowest level of Cx43 mRNA. The RT-PCR results of the microdissected segments correlate well with those obtained by RT-PCR of the renal regions. The high concentration of Cx43 mRNA in the IMCD together with the observation of abundant punctate immunofluorescence for Cx43 suggests that the IMCD not only expresses Cx43 mRNA but also that the mRNA is translated to Cx43 protein.
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Johal, Jasbir S., James W. Thorp, and Calvin E. Oyer. "Neonatal Hemochromatosis, Renal Tubular Dysgenesis, and Hypocalvaria in a Neonate." Pediatric and Developmental Pathology 1, no. 5 (September 1998): 433–37. http://dx.doi.org/10.1007/s100249900059.
Full textAbstract:
We report a neonate with neonatal hemochromatosis (NH), renal tubular dysgenesis (RTD), and hypocalvaria. NH is a fatal condition of the newborn, characterized by severe idiopathic liver failure of intrauterine onset and siderosis, intra- and extrahepatic, with sparing of the reticuloendothelial system. RTD is characterized by short, abnormally developed cortical tubules that lack proximal tubule differentiation. Although both NH and RTD have been reported as entities with a genetic component, similar findings can be secondary to in utero insults. Hypocalvaria has been reported in association with fetal hypoxia including that secondary to angiotensin converting enzyme inhibitors. This 38-week-old infant died at 8.5 h. The small nodular liver weighed 44 g. Grossly, the kidneys were normal. Hypocalvaria was present. Microscopically, the hepatic parenchyma was distorted by fibrous tracts, proliferation of bile ducts, and abundant iron deposition in hepatocytes. Extrahepatic siderosis in the pancreas, myocardium, and other organs was consistent with NH. Proximal convoluted tubules were not seen on routine stains and markers for proximal tubules were negative. Previous reports have linked NH with RTD and RTD with hypocalvaria. This infant had all three of these rare conditions, which have been hypothesized or shown to be due to genetic factors, hypoxia, or drugs. The etiology in this case is unknown.
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Morishita, Yoshiyuki, Toshiyuki Matsuzaki, Mariko Hara-chikuma, Ayaka Andoo, Mariko Shimono, Asako Matsuki, Katsuki Kobayashi, et al. "Disruption of Aquaporin-11 Produces Polycystic Kidneys following Vacuolization of the Proximal Tubule." Molecular and Cellular Biology 25, no. 17 (September 1, 2005): 7770–79. http://dx.doi.org/10.1128/mcb.25.17.7770-7779.2005.
Full textAbstract:
ABSTRACT Aquaporin-11 (AQP11) has been identified with unusual pore-forming NPA (asparagine-proline-alanine) boxes, but its function is unknown. We investigated its potential contribution to the kidney. Immunohistochemistry revealed that AQP11 was localized intracellularly in the proximal tubule. When AQP11 was transfected in CHO-K1 cells, it was localized in intracellular organelles. AQP11-null mice were generated; these mice exhibited vacuolization and cyst formation of the proximal tubule. AQP11-null mice were born normally but died before weaning due to advanced renal failure with polycystic kidneys, in which cysts occupied the whole cortex. Remarkably, cyst epithelia contained vacuoles. These vacuoles were present in the proximal tubules of newborn mice. In 3-week-old mice, these tubules contained multiple cysts. Primary cultured cells of the proximal tubule revealed an endosomal acidification defect in AQP11-null mice. These data demonstrate that AQP11 is essential for the proximal tubular function. AQP11-null mice are a novel model for polycystic kidney diseases and will provide a new mechanism for cystogenesis.
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Li, Huiping, Eric T. Weatherford, Deborah R. Davis, Henry L. Keen, Justin L. Grobe, Alan Daugherty, Lisa A. Cassis, Andrew M. Allen, and Curt D. Sigmund. "Renal proximal tubule angiotensin AT1A receptors regulate blood pressure." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301, no. 4 (October 2011): R1067—R1077. http://dx.doi.org/10.1152/ajpregu.00124.2011.
Full textAbstract:
All components of the renin angiotensin system necessary for ANG II generation and action have been reported to be present in renal proximal convoluted tubules. Given the close relationship between renal sodium handling and blood pressure regulation, we hypothesized that modulating the action of ANG II specifically in the renal proximal tubules would alter the chronic level of blood pressure. To test this, we used a proximal tubule-specific, androgen-dependent, promoter construct (KAP2) to generate mice with either overexpression of a constitutively active angiotensin type 1A receptor transgene or depletion of endogenous angiotensin type 1A receptors. Androgen administration to female transgenic mice caused a robust induction of the transgene in the kidney and increased baseline blood pressure. In the receptor-depleted mice, androgen administration to females resulted in a Cre recombinase-mediated deletion of angiotensin type 1A receptors in the proximal tubule and reduced blood pressure. In contrast to the changes observed at baseline, there was no difference in the blood pressure response to a pressor dose of ANG II in either experimental model. These data, from two separate mouse models, provide evidence that ANG II signaling via the type 1A receptor in the renal proximal tubule is a regulator of systemic blood pressure under baseline conditions.
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Padanilam, B. J., and M. R. Hammerman. "Ischemia-induced receptor for activated C kinase (RACK1) expression in rat kidneys." American Journal of Physiology-Renal Physiology 272, no. 2 (February 1, 1997): F160—F166. http://dx.doi.org/10.1152/ajprenal.1997.272.2.f160.
Full textAbstract:
Differential display-polymerase chain reaction (DD-PCR) was used to identify genes that are expressed in kidney following induction of acute ischemic renal injury. The receptor for activated C kinase (RACK1) mRNA expression in kidneys obtained from rats 12 h following ischemia is enhanced twofold compared with sham-operated rats. The maximal enhancement of expression (3.3-fold) is at 7 days following reperfusion. Expression remains elevated at 14 days. RACK1 transcripts and protein are localized to the damaged and regenerating segments of proximal tubules. At 1 day following injury, RACK1 protein is present in the epithelial cells of the damaged S3 segment and in cells sloughed into the tubular lumen. By 5 days following injury, RACK1 protein expression is enhanced in the regenerating cells relining the injured tubules of the S3 segment and in papillary proliferations within regenerating tubules. Increased expression of RACK1 could enhance the activity of PKC and, in so doing, regulate the process of regeneration of the proximal tubule following ischemic renal injury.
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Wright, P. A., and M. A. Knepper. "Glutamate dehydrogenase activities in microdissected rat nephron segments: effects of acid-base loading." American Journal of Physiology-Renal Physiology 259, no. 1 (July 1, 1990): F53—F59. http://dx.doi.org/10.1152/ajprenal.1990.259.1.f53.
Full textAbstract:
A method for measurement of glutamate dehydrogenase (GDH) activity in single renal tubules was employed to determine the distribution and regulation of GDH in tubule segments. Fresh microdissected tubules from collagenase-treated kidneys were permeabilized by hyposmotic shock and freezing. The rate of conversion of alpha-ketoglutarate, NH4+, and NADH to glutamate and NAD was measured at 37 degrees C fluorometrically. Very high activities were found in proximal tubule segments (150-210 pmol.min-1.mm tubule length-1), intermediate values (40-90 pmol.min-1.mm-1) in distal convoluted tubules, cortical thick ascending limbs, connecting tubules, medullary thick ascending limbs, and lower values (5-30 pmol.min-1.mm-1) in cortical collecting ducts, inner medullary collecting ducts, outer medullary collecting ducts, outer medullary thin limbs, and inner medullary thin limbs. To determine the effects of acid-base loading on GDH activity, 0.28 M NH4Cl (acid) or 0.28 M NaHCO3 (alkali) was added to the animals' drinking water for 7 days. Acid intake by the rats increased GDH activity in S1 and S2 proximal tubules by threefold, with no effect in other segments, including S3 proximal tubules. Alkali intake decreased GDH activity in the S3 proximal tubule by 40%, with no effect in other segments. We conclude that GDH activities are highest in proximal tubule segments and are regulated only in proximal tubule segments. Thus the results are consistent with the view that the proximal tubule is the chief site of the regulated production of ammonium in the kidney.
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Ricardo, S. D., G. Ding, M. Eufemio, and J. R. Diamond. "Antioxidant expression in experimental hydronephrosis: role of mechanical stretch and growth factors." American Journal of Physiology-Renal Physiology 272, no. 6 (June 1, 1997): F789—F798. http://dx.doi.org/10.1152/ajprenal.1997.272.6.f789.
Full textAbstract:
We assessed whether levels of renal reactive oxygen species (ROS) and antioxidant enzymes are perturbed in rats following unilateral ureteral obstruction (UUO). The mechanism of catalase perturbation was investigated using proximal tubule suspensions following stimulation with transforming growth factor (TGF)-beta and interleukin (IL)-1 and in a proximal tubular cell line (OKC) subjected to cyclic mechanical stretch, which mimics the early hydrodynamic derangement after UUO. Levels of catalase and copperzinc superoxide dismutase (Cu,Zn-SOD) mRNA from 96-h UUO rats showed a 5.5-fold (P < 0.001) and 5.0-fold (P < 0.001) decrease, respectively, compared with the contralateral unobstructed kidney (CUK). Levels of superoxide anion and hydrogen peroxide showed a significant 1.8-fold (P < 0.0001) and 14.0-fold (P < 0.0001) increase, respectively, in 96-h UUO kidney slice cultures. In situ hybridization and immunohistochemistry showed Cu,Zn-SOD and catalase mRNA and protein transcription expressed in proximal tubules of UUO and CUK specimens. Catalase mRNA levels were markedly downregulated following a 1-h exposure of isolated proximal tubules to TGF-beta (0.1–10 ng) and IL-1 (1–5 ng), in comparison to control proximal tubular suspensions. OKC subjected to cyclic mechanical stretch for 1–24 h had marked decrements in catalase mRNA levels, compared with unstretched cells at the same time point. These results indicate that a primary downregulation of proximal tubular Cu,Zn-SOD and catalase expression develops in the proximal tubules of UUO with consequent increments in cortical oxidant levels. These findings suggest that either an early mechanical disturbance produced by UUO or local tubular generation of cytokines can reduce tubular catalase expression. The downregulation of catalase mRNA expression, together with increased oxidant stress in the rat renal cortex post-UUO, may amplify the proinflammatory state of experimental hydronephrosis culminating in tubulointerstitial injury and fibrosis.
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Stokes, T. J., C. L. McConkey, and K. J. Martin. "Atriopeptin III increases cGMP in glomeruli but not in proximal tubules of dog kidney." American Journal of Physiology-Renal Physiology 250, no. 1 (January 1, 1986): F27—F31. http://dx.doi.org/10.1152/ajprenal.1986.250.1.f27.
Full textAbstract:
Atriopeptin III is natriuretic, diuretic, and phosphaturic in the intact dog and relaxes vascular and nonvascular smooth muscle in vitro. The mechanism of the renal effects of atriopeptin remains ill defined but may include hemodynamic alterations and/or direct tubular effects. Since many peptide hormones act through changes in cyclic nucleotide formation, we examined the effect of synthetic atriopeptins on cAMP and cGMP accumulation in isolated glomeruli and proximal tubules from normal dog kidney. Synthetic atriopeptin produced a dose-related increase in cGMP in glomeruli with a Kact of 200 +/- 19 nM and a maximal activity of 64.1 +/- 6.3 pmol cGMP X mg prot-1 X 5 min-1. In the presence of 4 mM Mn2+ Kact was reduced to 19 +/- 2 nM with no change in maximal cGMP production (66.2 +/- 11.8 pmol cGMP X mg prot-1 X 5 min-1). Atriopeptin (1 microM) did not increase cGMP accumulation above basal levels in proximal tubule segments. The cAMP production of neither glomeruli nor proximal tubules was stimulated by atriopeptin. These studies demonstrate a dose-dependent stimulation of guanylate cyclase by atriopeptin in glomeruli but not in proximal tubule segments. In addition, atriopeptin neither stimulates nor inhibits cAMP accumulation in glomeruli or proximal tubules. These data suggest a major role for the renal effects of atriopeptin at the glomerular level, possibly through hemodynamic effects or changes in the glomerular ultrafiltration coefficient.(ABSTRACT TRUNCATED AT 250 WORDS)
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Kim, Y. K., and W. H. Dantzler. "Intracellular pH in snake renal proximal tubules." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 269, no. 4 (October 1, 1995): R822—R829. http://dx.doi.org/10.1152/ajpregu.1995.269.4.r822.
Full textAbstract:
Intracellular pH (pHi) was studied in isolated proximal renal tubules of garter snakes (Thamnophis spp.) with oil-filled lumens under control conditions [N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered medium with pH 7.4 at 25 degrees C] and in response to NH4Cl pulse. pHi was measured with the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorescein (BCECF). Control resting pHi (7.1) and acidification in response to NH4Cl pulse (minimum pHi, 6.6) were essentially the same in snake tubules with oil-filled lumens or perfused lumens and in rabbit S2 proximal tubules with oil-filled lumens. Rate of recovery of pHi (dpHi/dt) from acid to resting level in snake tubules (2.5 x 10(-3) pH U/s was about one-third of that in rabbit tubules. Resting pHi and dpHi/dt from acid to resting level were Na+ dependent in the distal portion but not the proximal portion of snake proximal tubules. However, dpHi/dt was not influenced by amiloride or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid in snake proximal tubules, suggesting that the effect of Na+ on dpHi/dt and resting pHi may involve membrane potential. This study also indicates that oil-filled lumens do not interfere with measurements of resting pHi and do permit evaluation of pHi regulation at the basolateral membrane without complications from transport at the luminal membrane.
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Yanagawa, Norimoto, Remi N. G. Shih, Oak D. Jo, and Hamid M. Said. "Riboflavin transport by isolated perfused rabbit renal proximal tubules." American Journal of Physiology-Cell Physiology 279, no. 6 (December 1, 2000): C1782—C1786. http://dx.doi.org/10.1152/ajpcell.2000.279.6.c1782.
Full textAbstract:
Rabbit renal proximal tubular transport of riboflavin (RF) was examined by using the in vitro isolated tubule perfusion technique. We found that proximal tubules actively reabsorbed ( J lb) and secreted ( J bl) RF. At 0.1 μM RF concentration, J bl was significantly higher than J lb, resulting in a net secretion. This net secretion of RF was decreased at 0.01 μM RF concentration and increased at 1 μM RF concentration. Both J lb and J bl were inhibited by lowering temperature or by adding iodoacetate, a metabolic inhibitor, and lumichrome, an RF analog, suggesting the involvement of carrier-mediated transport mechanisms. J bl was inhibited by probenecid, an anion transport inhibitor, and by para-aminohippuric acid, an organic anion, suggesting the relevance of RF secretion to renal organic anion transport. J bl was also inhibited by alkaline pH (8.0) and by the calmodulin inhibitor trifluoperazine, indicating the influence of pH and Ca2+/calmodulin-dependent pathway on RF secretion. Finally, we found that addition of chlorpromazine, a phenothiazine derivative, inhibited both J lb and J bl, raising the concern about the nutritional status in patients receiving such a type of medication.