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Journal articles on the topic 'Experimental C-peptide Kidney'
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Jeson Sangaralingham, S., Denise M. Heublein, Joseph P. Grande, et al. "Urinary C-type natriuretic peptide excretion: a potential novel biomarker for renal fibrosis during aging." American Journal of Physiology-Renal Physiology 301, no. 5 (2011): F943—F952. http://dx.doi.org/10.1152/ajprenal.00170.2011.
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Renal aging is characterized by structural changes in the kidney including fibrosis, which contributes to the increased risk of kidney and cardiac failure in the elderly. Studies involving healthy kidney donors demonstrated subclinical age-related nephropathy on renal biopsy that was not detected by standard diagnostic tests. Thus there is a high-priority need for novel noninvasive biomarkers to detect the presence of preclinical age-associated renal structural and functional changes. C-type natriuretic peptide (CNP) possesses renoprotective properties and is present in the kidney; however, its modulation during aging remains undefined. We assessed circulating and urinary CNP in a Fischer rat model of experimental aging and also determined renal structural and functional adaptations to the aging process. Histological and electron microscopic analysis demonstrated significant renal fibrosis, glomerular basement membrane thickening, and mesangial matrix expansion with aging. While plasma CNP levels progressively declined with aging, urinary CNP excretion increased, along with the ratio of urinary to plasma CNP, which preceded significant elevations in proteinuria and blood pressure. Also, CNP immunoreactivity was increased in the distal and proximal tubules in both the aging rat and aging human kidneys. Our findings provide evidence that urinary CNP and its ratio to plasma CNP may represent a novel biomarker for early age-mediated renal structural alterations, particularly fibrosis. Thus urinary CNP could potentially aid in identifying subjects with preclinical structural changes before the onset of symptoms and disease, allowing for the initiation of strategies designed to prevent the progression of chronic kidney disease particularly in the aging population.
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Nordquist, Lina, Russell Brown, Angelica Fasching, Patrik Persson, and Fredrik Palm. "Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption." American Journal of Physiology-Renal Physiology 297, no. 5 (2009): F1265—F1272. http://dx.doi.org/10.1152/ajprenal.00228.2009.
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C-peptide reduces diabetes-induced glomerular hyperfiltration in diabetic patients and experimental animal models. However, the mechanisms mediating the beneficial effect of C-peptide remain unclear. We investigated whether altered renal afferent-efferent arteriole tonus or alterations in tubular Na+ transport (TNa) in response to C-peptide administration mediate the reduction of diabetes-induced glomerular hyperfiltration. Glomerular filtration rate, filtration fraction, total and cortical renal blood flow, total kidney O2 consumption (Qo2), TNa, fractional Na+ and Li+ excretions, and tubular free-flow and stop-flow pressures were measured in anesthetized adult male normoglycemic and streptozotocin-diabetic Sprague-Dawley rats. The specific effect of C-peptide on transport-dependent Qo2 was investigated in vitro in freshly isolated proximal tubular cells. C-peptide reduced glomerular filtration rate (−24%), stop-flow pressure (−8%), and filtration fraction (−17%) exclusively in diabetic rats without altering renal blood flow. Diabetic rats had higher baseline TNa (+40%), which was reduced by C-peptide. Similarly, C-peptide increased fractional Na+ (+80%) and Li+ (+47%) excretions only in the diabetic rats. None of these parameters was affected by vehicle treatments in either group. Baseline Qo2 was 37% higher in proximal tubular cells from diabetic rats than controls and was normalized by C-peptide. C-peptide had no effect on ouabain-pretreated diabetic cells from diabetic rats. C-peptide reduced diabetes-induced hyperfiltration via a net dilation of the efferent arteriole and inhibition of tubular Na+ reabsorption, both potent regulators of the glomerular net filtration pressure. These findings provide new mechanistic insight into the beneficial effects of C-peptide on diabetic kidney function.
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Schiffrin, Ernesto L. "Vascular receptors for angiotensin, vasopressin, and atrial natriuretic peptide in experimental hypertension." Canadian Journal of Physiology and Pharmacology 67, no. 9 (1989): 1118–23. http://dx.doi.org/10.1139/y89-178.
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Angiotensin II (ANG II) and vasopressin (AVP) are two powerful vasoconstrictors, and atrial natriuretic peptide (ANP) is a potent vasorelaxant. The changes in the density or affinity of binding sites for these agents that may alter target organ responsiveness in hypertension are reviewed. ANG II binding in mesenteric arteries was unaltered in one-kidney, one-clip (1-K, 1-C) and in 2-K,1-C hypertensive rats, while in deoxycorticosterone acetate (DOCA)-salt hypertensive rats ANG II binding to blood vessels was significantly increased. A role of mineralocorticoids to increase the number of vascular ANG II sites in some hypertensive models is suggested. In spontaneously hypertensive rats (SHR) ANG II receptors were increased in young rats in the prehypertensive stage with respect to Wistar–Kyoto (WKY) control rats, but normal in older rats. AVP binding in the vasculature of hypertensive rats was uniformly decreased in inverse correlation to plasma AVP levels, but vascular responsiveness to AVP was exaggerated. Inositol trisphosphate production by blood vessels of SHR in response to AVP showed that increased AVP receptor-coupled phospholipase C activity may mediate in part the exaggerated pressor response in spite of reduced or normal density of receptors for vasoconstrictor peptides. Vascular ANP sites in 2-K, 1-C, 1-K, 1-C, and DOCA-salt hypertensive rats varied inversely with plasma concentrations of ANP. Normal densities of ANP receptors in saralasin-sensitive 2-K, 1-C hypertensive rats correlated with ANP sensitivity, while saralasin-insensitive 2-K, 1-C hypertensive rats, which did not respond to ANP, had significantly decreased density of ANP vascular receptors. Receptor number in SHR did not vary inversely with plasma levels of ANP, in contrast to other hypertensive models. In experimental and spontaneous hypertensive rat models there are various abnormalities in the regulation of vascular binding sites for peptides (ANG II, AVP, and ANP) and in the coupling of receptors to intracellular signal transduction mechanisms, which may play a role in the development and maintenance of high blood pressure.Key words: receptor regulation, vasoactive peptides, blood vessels, high blood pressure.
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Fraenkel, Margaret B., G. Peter Aldred, and John G. McDougall. "Sodium Status Affects Gc-B Natriuretic Peptide Receptor mRNA Levels, but Not Gc-A Or C Receptor Mrna Levels, in the Sheep Kidney." Clinical Science 86, no. 5 (1994): 517–22. http://dx.doi.org/10.1042/cs0860517.
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1. In humans and experimental animals the natriuresis and diuresis resulting from infusion of atrial natriuretic peptide varies with the sodium status of the subject. Tissue binding studies have suggested that this may be related to changes in the renal receptors for the hormone. 2. In order to establish whether these changes are under transcriptional control, we examined the levels of mRNA for the three natriuretic peptide receptors [GC-A, GC-B and clearance (C) receptors] in renal cortex and medulla from six sodium-loaded, six sodium-depleted and four control sheep. cDNA probes specific to each receptor were generated using the polymerase chain reaction. 3. GC-B receptor mRNA levels were increased approximately two-fold in the renal cortex of sodium-depleted animals, whereas there was no influence on GC-B receptor mRNA levels in the renal medulla. There was no significant difference in mRNA levels for the GC-A and C receptors. 4. At present the role of the GC-B receptor and its natural ligand C-type natriuretic peptide in the control of renal function is unknown. The present experiments imply some intrarenal function for the GC-B receptor and its natural ligand, although the site of any such function, e.g. renal vasculature or tubules, remains unclear. In addition, we have shown that if GC-A and C receptor levels in the sheep are modulated by sodium, the regulation occurs beyond the level of gene transcription.
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Prickett, Timothy C. R., Helen Lunt, Julie Warwick, Helen F. Heenan, and Eric A. Espiner. "Urinary Amino-Terminal Pro–C-Type Natriuretic Peptide: A Novel Marker of Chronic Kidney Disease in Diabetes." Clinical Chemistry 65, no. 10 (2019): 1248–57. http://dx.doi.org/10.1373/clinchem.2019.306910.
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Abstract BACKGROUND Chronic renal inflammation and fibrosis are common sequelae in diabetes mellitus (DM) and are major causes of premature mortality. Although upregulation of NPPC expression occurs in response to renal inflammation in experimental animals, nothing is known of the molecular forms of C-type natriuretic peptide (CNP) products in urine of people with DM or links with renal function. METHODS ProCNP products in urine were characterized with HPLC and a range of antisera directed to specific epitopes of amino-terminal proCNP (NTproCNP). The 5-kDa intact peptide was quantified in spot urine samples from healthy adults and 202 participants with DM selected to provide a broad range of renal function. RESULTS The predominant products of proCNP in urine were consistent with the 2-kDa fragment (proCNP 3–20) and a smaller peak of intact (5-kDa) fragment (proCNP 1–50, NTproCNP). No peaks consistent with bioactive forms (proCNP 82–103, 50–103) were identified. The urine NTproCNP to creatinine ratio (NCR) was more reproducible than the albumin to creatinine ratio (ACR) and strongly associated with the presence of chronic kidney disease. In models predicting independence, among 10 variables associated with renal function in DM, including plasma NTproCNP, only 3 (sex, ACR, and plasma creatinine) contributed to NCR. CONCLUSIONS Characterization of the products of proCNP in urine confirmed the presence of NTproCNP. In spot random urine from study participants with DM, NCR is inversely associated with estimated glomerular filtration rate. In contrast to ACR, NCR reflects nonvascular factors that likely include renal inflammation and fibrosis.
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Nikapitiya, Chamilani, S. H. S. Dananjaya, H. P. S. U. Chandrarathna, Mahanama De Zoysa, and Ilson Whang. "Octominin: A Novel Synthetic Anticandidal Peptide Derived from Defense Protein of Octopus minor." Marine Drugs 18, no. 1 (2020): 56. http://dx.doi.org/10.3390/md18010056.
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The rapid emergence of multidrug-resistant pathogens makes an urgent need for discovering novel antimicrobial agents as alternatives to conventional antibiotics. Towards this end, we designed and synthesized a synthetic peptide of 23 amino acids (AAs) (1GWLIRGAIHAGKAIHGLIHRRRH23) from a defense protein 3 cDNA sequence of Octopus minor. The sequence of the peptide, which was named Octominin, had characteristic features of known antimicrobial peptides (AMPs) such as a positive charge (+5), high hydrophobic residue ratio (43%), and 1.86 kcal/mol of Boman index. Octominin was predicted to have an alpha-helix secondary structure. The synthesized Octominin was 2625.2 Da with 92.5% purity. The peptide showed a minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of 50 and 200 μg/mL, respectively, against Candida albicans. Field emission scanning electron microscopy observation confirmed that Octominin caused ultrastructural cell wall deformities in C. albicans. In addition, propidium iodide penetrated the Octominin-treated C. albicans cells, further demonstrating loss of cell membrane integrity that caused cell death at both MIC and MFC. Octominin treatment increased the production of intracellular reactive oxygen species and decreased cell viability in a concentration dependent manner. Cytotoxicity assays revealed no significant influence of Octominin on the viability of human embryonic kidney 293T cell line, with over 95% live cells in the Octominin-treated group observed up to 100 µg/mL. Moreover, we confirmed the antifungal action of Octominin in vivo using a zebrafish experimental infection model. Overall, our results demonstrate the Octominin is a lead compound for further studies, which exerts its effects by inducing cell wall damage, causing loss of cell membrane integrity, and elevating oxidative stress.
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Chaturvedi, Ashok K., A. Kavishwar, G. B. Shiva Keshava, and P. K. Shukla. "Monoclonal Immunoglobulin G1 Directed against Aspergillus fumigatus Cell Wall Glycoprotein Protects against Experimental Murine Aspergillosis." Clinical Diagnostic Laboratory Immunology 12, no. 9 (2005): 1063–68. http://dx.doi.org/10.1128/cdli.12.9.1063-1068.2005.
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ABSTRACT Most of the biological functions related to pathogenicity and virulence reside in the fungal cell wall, which, being the outermost part of the cell, mediates the host-fungus interplay. For these reasons much effort has focused on the discovery of useful inhibitors of cell wall glucan, chitin, and mannoprotein biosynthesis. In the absence of a wide-spectrum, safe, and potent antifungal agent, a new strategy for antifungal therapy is directed towards the development of monoclonal antibodies (MAbs). In the present study the MAb A9 (immunoglobulin G1 [IgG1]) was identified from hybridomas raised in BALB/c mice immunized with cell wall antigen of Aspergillus fumigatus. The immunoreactive epitopes for this IgG1 MAb appeared to be associated with a peptide moiety, and indirect immunofluorescence microscopy revealed its binding to the cell wall surface of hyphae as well as with swollen conidia. MAb A9 inhibited hyphal development as observed by MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (25.76%), reduced the duration of spore germination, and exerted an in vitro cidal effect against Aspergillus fumigatus. The in vivo protective efficacy of MAb A9 was also evaluated in a murine model of invasive aspergillosis, where a reduction in CFU (>4 log10 units) was observed in kidney tissue of BALB/c mice challenged with A. fumigatus (2 × 105 CFU/ml) and where enhanced mean survival times (19.5 days) compared to the control (7.1 days) and an irrelevant MAb (6.1 days) were also observed.
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Hinkelbein, Jochen, Lennert Böhm, Stefan Braunecker, Christoph Adler, Edoardo De Robertis, and Fabrizio Cirillo. "Decreased Tissue COX5B Expression and Mitochondrial Dysfunction during Sepsis-Induced Kidney Injury in Rats." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–24. http://dx.doi.org/10.1155/2017/8498510.
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Background. Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host response to infection. Sepsis is the dominant cause of acute kidney injury (AKI), accounting for nearly 50% of episodes of acute renal failure. Signaling cascades and pathways within the kidney are largely unknown and analysis of these molecular mechanisms may enhance knowledge on pathophysiology and possible therapeutic options.Material and Methods. 26 male Wistar rats were assigned to either a sham group (control,N=6) or sepsis group (N=20; cecal ligature and puncture model, 24 and 48 hours after CLP). Surviving rats (n=12) were decapitated at 24 hours (early phase;n=6) or 48 hours (late phase;n=6) after CLP and kidneys removed for proteomic analysis. 2D-DIGE and DeCyder 2D software (t-test,P<0.01) were used for analysis of significantly regulated protein spots. MALDI-TOF in combination with peptide mass fingerprinting (PMF) as well as Western Blot analysis was used for protein identification. Bioinformatic network analyses (STRING, GeneMania, and PCViz) were used to describe protein-protein interactions.Results. 12 spots were identified with significantly altered proteins (P<0.01) in the three analyzed groups. Two spots could not be identified. Four different proteins were found significantly changed among the groups: major urinary protein (MUP5), cytochrome c oxidase subunit B (COX5b), myosin-6 (MYH6), and myosin-7 (MYH7). A significant correlation with the proteins was found for mitochondrial energy production and electron transport.Conclusions. COX5B could be a promising biomarker candidate since a significant association was found during experimental sepsis in the present study. For future research, COX5B should be evaluated as a biomarker in both human urine and serum to identify sepsis.
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Suman, Rajesh Kumar, Ipseeta Ray Mohanty, Manjusha K. Borde, Ujwala Maheshwari, and Y. A. Deshmukh. "Development of an Experimental Model of Diabetes Co-Existing with Metabolic Syndrome in Rats." Advances in Pharmacological Sciences 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/9463476.
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Background. The incidence of metabolic syndrome co-existing with diabetes mellitus is on the rise globally.Objective. The present study was designed to develop a unique animal model that will mimic the pathological features seen in individuals with diabetes and metabolic syndrome, suitable for pharmacological screening of drugs.Materials and Methods. A combination of High-Fat Diet (HFD) and low dose of streptozotocin (STZ) at 30, 35, and 40 mg/kg was used to induce metabolic syndrome in the setting of diabetes mellitus in Wistar rats.Results. The 40 mg/kg STZ produced sustained hyperglycemia and the dose was thus selected for the study to induce diabetes mellitus. Various components of metabolic syndrome such as dyslipidemia(increased triglyceride, total cholesterol, LDL cholesterol, and decreased HDL cholesterol), diabetes mellitus (blood glucose, HbA1c, serum insulin, and C-peptide), and hypertension{systolic blood pressure}were mimicked in the developed model of metabolic syndrome co-existing with diabetes mellitus. In addition to significant cardiac injury, atherogenic index, inflammation (hs-CRP), decline in hepatic and renal function were observed in the HF-DC group when compared to NC group rats. The histopathological assessment confirmed presence of edema, necrosis, and inflammation in heart, pancreas, liver, and kidney of HF-DC group as compared to NC.Conclusion. The present study has developed a unique rodent model of metabolic syndrome, with diabetes as an essential component.
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Rajasekaran, Narmadha, Gomathi Duraisamy, Kalaiselvi Manokaran, and Devaki Kanakasapathi. "In Vivo Assessment of Antioxidants and Antihyperglycemic Effect of Barleria cristata leaves in Streptozotocin- Induced Diabetic Rats." International Journal of Applied Sciences and Biotechnology 2, no. 4 (2014): 437–45. http://dx.doi.org/10.3126/ijasbt.v2i4.11219.
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Objective: Many new bioactive drugs isolated from plants having hypoglycaemic effects showed anti diabetic activity equal and sometimes even more potent than known oral hypoglycaemic agents. In this present study, designed to evaluate antihyperglycermic and antioxidants effect on ethanolic leaf extracts Barleria cristata (EtBc) in streptozotocin-induced diabetic rats at dose level 400mg/kg body weight for the treatment of 45 days. Method and materials: The experimental rats were randomly divided into five groups as a control, streptozotocin induced with diabetes (45mg/kg bw) without any treatment, treated with standard drug glibenclamide (1.25 mg/kg bw), EtBc (400 mg/kg bw) in diabetic induced rats and treated with EtBc alone without diabetic rats. At the end of 45th day animals were sacrificed, collect the serum, liver, kidney and pancreas for estimate the glucose, insulin, C-peptide, glycosylated hemoglobin, hemoglobin in serum, protein, enzymatic and nonenzymatic antioxidants and lipid peroxidation in tissues. Results: After the administration of EtBc, blood glucose levels were showed significantly reduction (P<0.05) in diabetic rats and it has been observed alternation occured in body and organ weight and it was also normalized the serum level of glycemic profile like insulin, C-peptide, total hemoglobin and glycosylated hemoglobin levels similar to that of control rats. Antioxidants enzymes were return to back their levels as control in different tissues when compared to diabetic rats and also observed no significance difference between control and EtBc alone group rats at the end of 45th day. Therefore it was suggested that Barleria cristata may act by potentiation of pancreatic secretion of insulin or increasing glucose uptake by muscle cells. Conclusion: In this study, suggested the efficacy of Barleria cristata proved the maintenance of glucose homeostasis and may be used as a therapeutic agent in the management of diabetes mellitus.DOI: http://dx.doi.org/10.3126/ijasbt.v2i4.11219 Int J Appl Sci Biotechnol, Vol. 2(4): 437-445
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Chua, Winnie, Jonathan P. Law, Victor R. Cardoso, et al. "Quantification of fibroblast growth factor 23 and N-terminal pro-B-type natriuretic peptide to identify patients with atrial fibrillation using a high-throughput platform: A validation study." PLOS Medicine 18, no. 2 (2021): e1003405. http://dx.doi.org/10.1371/journal.pmed.1003405.
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Background Large-scale screening for atrial fibrillation (AF) requires reliable methods to identify at-risk populations. Using an experimental semi-quantitative biomarker assay, B-type natriuretic peptide (BNP) and fibroblast growth factor 23 (FGF23) were recently identified as the most suitable biomarkers for detecting AF in combination with simple morphometric parameters (age, sex, and body mass index [BMI]). In this study, we validated the AF model using standardised, high-throughput, high-sensitivity biomarker assays. Methods and findings For this study, 1,625 consecutive patients with either (1) diagnosed AF or (2) sinus rhythm with CHA2DS2-VASc score of 2 or more were recruited from a large teaching hospital in Birmingham, West Midlands, UK, between September 2014 and February 2018. Seven-day ambulatory ECG monitoring excluded silent AF. Patients with tachyarrhythmias apart from AF and incomplete cases were excluded. AF was diagnosed according to current clinical guidelines and confirmed by ECG. We developed a high-throughput, high-sensitivity assay for FGF23, quantified plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and FGF23, and compared results to the previously used multibiomarker research assay. Data were fitted to the previously derived model, adjusting for differences in measurement platforms and known confounders (heart failure and chronic kidney disease). In 1,084 patients (46% with AF; median [Q1, Q3] age 70 [60, 78] years, median [Q1, Q3] BMI 28.8 [25.1, 32.8] kg/m2, 59% males), patients with AF had higher concentrations of NT-proBNP (median [Q1, Q3] per 100 pg/ml: with AF 12.00 [4.19, 30.15], without AF 4.25 [1.17, 15.70]; p < 0.001) and FGF23 (median [Q1, Q3] per 100 pg/ml: with AF 1.93 [1.30, 4.16], without AF 1.55 [1.04, 2.62]; p < 0.001). Univariate associations remained after adjusting for heart failure and estimated glomerular filtration rate, known confounders of NT-proBNP and FGF23. The fitted model yielded a C-statistic of 0.688 (95% CI 0.656, 0.719), almost identical to that of the derived model (C-statistic 0.691; 95% CI 0.638, 0.744). The key limitation is that this validation was performed in a cohort that is very similar demographically to the one used in model development, calling for further external validation. Conclusions Age, sex, and BMI combined with elevated NT-proBNP and elevated FGF23, quantified on a high-throughput platform, reliably identify patients with AF. Trial registration Registry IRAS ID 97753 Health Research Authority (HRA), United Kingdom
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Poteryaeva, O. N., and I. F. Usynin. "Molecular mechanisms of action and physiological effects of the proinsulin C-peptide (a systematic review)." Biomeditsinskaya Khimiya 66, no. 3 (2020): 196–207. http://dx.doi.org/10.18097/pbmc20206603196.
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The C-peptide is a fragment of proinsulin, the cleavage of which forms active insulin. In recent years, new information has appeared on the physiological effects of the C-peptide, indicating its positive effect on many organs and tissues, including the kidneys, nervous system, heart, vascular endothelium and blood microcirculation. Studies on experimental models of diabetes mellitus in animals, as well as clinical trials in patients with diabetes, have shown that the C-peptide has an important regulatory effect on the early stages of functional and structural disorders caused by this disease. The C-peptide exhibits its effects through binding to a specific receptor on the cell membrane and activation of downstream signaling pathways. Intracellular signaling involves G-proteins and Ca2+-dependent pathways, resulting in activation and increased expression of endothelial nitric oxide synthase, Na+/K+-ATPase and important transcription factors involved in apoptosis, anti-inflammatory and other intracellular defense mechanisms. This review gives an idea of the C-peptide as a bioactive endogenous peptide that has its own biological activity and therapeutic potential.
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Ryk, Aleksandra, Aleksandra Łosiewicz, Arkadiusz Michalak, and Wojciech Fendler. "Biological Activity of c-Peptide in Microvascular Complications of Type 1 Diabetes—Time for Translational Studies or Back to the Basics?" International Journal of Molecular Sciences 21, no. 24 (2020): 9723. http://dx.doi.org/10.3390/ijms21249723.
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People with type 1 diabetes have an increased risk of developing microvascular complications, which have a negative impact on the quality of life and reduce life expectancy. Numerous studies in animals with experimental diabetes show that c-peptide supplementation exerts beneficial effects on diabetes-induced damage in peripheral nerves and kidneys. There is substantial evidence that c-peptide counteracts the detrimental changes caused by hyperglycemia at the cellular level, such as decreased activation of endothelial nitric oxide synthase and sodium potassium ATPase, and increase in formation of pro-inflammatory molecules mediated by nuclear factor kappa-light-chain-enhancer of activated B cells: cytokines, chemokines, cell adhesion molecules, vascular endothelial growth factor, and transforming growth factor beta. However, despite positive results from cell and animal studies, no successful c-peptide replacement therapies have been developed so far. Therefore, it is important to improve our understanding of the impact of c-peptide on the pathophysiology of microvascular complications to develop novel c-peptide-based treatments. This article aims to review current knowledge on the impact of c-peptide on diabetic neuro- and nephropathy and to evaluate its potential therapeutic role.
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ROBERTSON, Alexis, Gavin S. MacCOLL, Julia A. B. NASH, Mark K. BOEHM, Stephen J. PERKINS, and Pierre-Marc G. BOULOUX. "Molecular modelling and experimental studies of mutation and cell-adhesion sites in the fibronectin type III and whey acidic protein domains of human anosmin-1." Biochemical Journal 357, no. 3 (2001): 647–59. http://dx.doi.org/10.1042/bj3570647.
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Anosmin-1, the gene product of the KAL gene, is implicated in the pathogenesis of X-linked Kallmann's syndrome. Anosmin-1 protein expression is restricted to the basement membrane and interstitial matrix of tissues affected in this syndrome during development. The anosmin-1 sequence indicates an N-terminal cysteine-rich domain, a whey acidic protein (WAP) domain, four fibronectin type III (FnIII) domains and a C-terminal histidine-rich region, and shows similarity with cell-adhesion molecules, such as neural cell-adhesion molecule, TAG-1 and L1. We investigated the structural and functional significance of three loss-of-function missense mutations of anosmin-1 using comparative modelling of the four FnIII and the WAP domains based on known NMR and crystal structures. Three missense mutation-encoded amino acid substitutions, N267K, E514K and F517L, were mapped to structurally defined positions on the GFCC′ β-sheet face of the first and third FnIII domains. Electrostatic maps demonstrated large basic surfaces containing clusters of conserved predicted heparan sulphate-binding residues adjacent to these mutation sites. To examine these modelling results anosmin-1 was expressed in insect cells. The incorporation of the three mutations into recombinant anosmin-1 had no effect on its secretion. The removal of two dibasic motifs that may constitute potential physiological cleavage sites for anosmin-1 had no effect on cleavage. Peptides based on the anosmin-1 sequences R254–K285 and P504–K527 were then synthesized in order to assess the effect of the three mutations on cellular adhesion, using cell lines that represented potential functional targets of anosmin-1. Peptides (10μg/ml) incorporating the N267K and E514K substitutions promoted enhanced adhesion to 13.S.1.24 rat olfactory epithelial cells and canine MDCK1 kidney epithelial cells (P<0.01) compared with the wild-type peptides. This result was attributed to the introduction of a lysine residue adjacent to the large basic surfaces. We predict that two of the three missense mutants increase the binding of anosmin-1 to an extracellular target, possibly by enhancing heparan sulphate binding, and that this critically affects the function of anosmin-1.
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Zhao, Chengquan, Tung Nguyen, Lide Liu, Randy E. Sacco, Kim A. Brogden та Robert I. Lehrer. "Gallinacin-3, an Inducible Epithelial β-Defensin in the Chicken". Infection and Immunity 69, № 4 (2001): 2684–91. http://dx.doi.org/10.1128/iai.69.4.2684-2691.2001.
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ABSTRACT Gallinacin-3 and gallopavin-1 (GPV-1) are newly characterized, epithelial β-defensins of the chicken (Gallus gallus) and turkey (Meleagris gallopavo), respectively. In normal chickens, the expression of gallinacin-3 was especially prominent in the tongue, bursa of Fabricius, and trachea. It also occurred in other organs, including the skin, esophagus, air sacs, large intestine, and kidney. Tracheal expression of gallinacin-3 increased significantly after experimental infection of chickens with Haemophilus paragallinarum, whereas its expression in the tongue, esophagus, and bursa of Fabricius was unaffected. The precursor of gallinacin-3 contained a long C-terminal extension not present in the prepropeptide. By comparing the cDNA sequences of gallinacin-3 and GPV-1, we concluded that a 2-nucleotide insertion into the gallinacin-3 gene had induced a frameshift that read through the original stop codon and allowed the chicken propeptide to lengthen. The striking structural resemblance of the precursors of β-defensins to those of crotamines (highly toxic peptides found in rattlesnake venom) supports their homology, even though defensins are specialized to kill microorganisms and crotamines are specialized to kill much larger prey.
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Berdel, Wolfgang E., Torsten Kessler, Christian Schwöppe, et al. "Targeting Tissue Factor to Tumor Vessels. Experimental Results and First-in-Man Experience." Blood 114, no. 22 (2009): 469. http://dx.doi.org/10.1182/blood.v114.22.469.469.
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Abstract Abstract 469 Activation of blood coagulation in tumor vessels with subsequent tumor infarction is an experimental strategy in cancer therapy. We have fused different targeting peptides, including GRGDSP (RGD), GNGRAHA (NGR) and 5 cyclic derivates to the C-terminus of truncated tissue factor (tTF) to preferentially target tumor vessel endothelial cell integrins such as αvβ3 or aminopeptidase (CD13). tTF fusion proteins were expressed in E. coli, purified and refolded. Molecular integrity of the fusion proteins was evaluated by SDS-PAGE, immunoblotting and mass spectrometry. Subsequently, the tTF-fusion proteins were tested for biological activity with the following results: They retained the thrombogenic activity of tTF as measured by factor × activation in vitro. When tested with their respective target molecules either in a purified preparation or present on growing endothelial cells, there was specific binding. In vivo studies with human tumor xenograft models in nude mice showed either significant inhibition of tumor growth or regression of established tumors of different histologies (e.g. lung, breast, melanoma, sarcoma) by systemic application of the tTF-fusion proteins in contrast to controls including non-targeted tTF. Histology of the tumors treated with tTF fusion proteins revealed thrombotic occlusion of vasculature and blood pooling. Contrast-enhanced magnetic resonance imaging (MRI) of the tumors in vivo before and shortly after application of tTF-RGD and tTF-NGR showed a significant reduction of tumor perfusion. Degree of reduction correlated with in vivo tumor response. Toxicity studies showed acceptable therapeutic range and at therapeutic dosage there was no thrombo-embolic event in histology of normal organs, such as lung, heart, liver, and kidney. After upscaling production to amounts sufficient for clinical use, we have treated the first cancer patients with tTF-NGR. MRI studies even at the lowest dose (1 mg/kg i.v.) given showed reduction of tumor perfusion with no side effects. Targeted infarction of tumor vasculature with tTF fusion proteins may be promising as cancer therapy and should be further studied. Disclosures: Berdel: private: patent application on targeting tissue factor. Mesters:private: patent application on targeting tissue factor.
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Banti, Rafael S., Rodrigo Yokota, Danielle S. Aragão, et al. "Abstract P104: Renin Angiotensin System (RAS) Modulation in Hypertension Program by Maternal Intrauterine Malnutrition." Hypertension 66, suppl_1 (2015). http://dx.doi.org/10.1161/hyp.66.suppl_1.p104.
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Intrauterine malnutrition (IM) during the early stages of development can alter the function of organs and tissues and can predict a lifetime of increased risk for adverse health outcomes, such as diabetes and hypertension. The kidney plays a key role in the development of hypertension programmed by IM, with the participation of the RAS. Our objectives were to study ACE activity and angiotensin peptides levels in tissues. Pregnants Wistar rats were separated into two groups: control group (C), fed ad libitum, and malnourished group (D) submitted to food restriction (diet 50% of the amount of feed consumed by the group C). After birth the offspring were kept as experimental groups C and D, respectively. At 4 months of age, the animals were sacrificed, heart and kidney tissues were collected to quantify angiotensin peptides and ACE activity. The offspring born with low birth weight. Kidney ACE activity was higher in group D compared to group C (299 ±86.7 vs. 253.4 ±84.82 mU/mg, p<0.05), differing from Heart (D versus C: 0.15 ± 0.08 vs. 0.24 ±0.09 mU/mg). Group D presented high blood pressure values compared to group C (140.6 ±2.8 vs. 124,3±2.6 mmHg). Kidney and heart Ang II levels were increased in group D being significant when compared to group C (238.26 ±25.1 vs. 161.85 ±45.6 pmol/g and 397.89±74.9 vs. 223.33±48.7 pmol/g, p<0.05, respectively). The same was observed for Ang I. The vasodilator peptide Ang1-7 levels in group D from kidney and heart were lower in comparison with group C, thus emphasizing an enabling environment for hypertension (220.74 ± 48.74 vs. 288.09 ± 47 pmol/g and 152.1±41.2 pmol/g vs. 228.93±41.2 pmol/g, p<0.05, respectively). Our results indicate that perturbed maternal nutritional status alters tissue RAS resulting in higher blood pressure in the offspring, demonstrated by increased renal ACE activity and Ang II levels, with reduced Ang 1-7. The increase of Ang I and II in the heart, despite low ACE activity in this tissue suggests the activation of RAS alternative pathways. This study describes for the first time that low levels of Ang 1-7 contributed to the early development of hypertension.
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Freitas, Camila G., Stella M. F. Lima, Mirna S. Freire, et al. "An Immunomodulatory Peptide Confers Protection in an Experimental Candidemia Murine Model." Antimicrobial Agents and Chemotherapy 61, no. 8 (2017). http://dx.doi.org/10.1128/aac.02518-16.
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ABSTRACT Fungal Candida species are commensals present in the mammalian skin and mucous membranes. Candida spp. are capable of breaching the epithelial barrier of immunocompromised patients with neutrophil and cell-mediated immune dysfunctions and can also disseminate to multiple organs through the bloodstream. Here we examined the action of innate defense regulator 1018 (IDR-1018), a 12-amino-acid-residue peptide derived from bovine bactenecin (Bac2A): IDR-1018 showed weak antifungal and antibiofilm activity against a Candida albicans laboratory strain (ATCC 10231) and a clinical isolate (CI) (MICs of 32 and 64 μg · ml−1, respectively), while 8-fold lower concentrations led to dissolution of the fungal cells from preformed biofilms. IDR-1018 at 128 μg · ml−1 was not hemolytic when tested against murine red blood cells and also has not shown a cytotoxic effect on murine monocyte RAW 264.7 and primary murine macrophage cells at the tested concentrations. IDR-1018 modulated the cytokine profile during challenge of murine bone marrow-derived macrophages with heat-killed C. albicans (HKCA) antigens by increasing monocyte chemoattractant protein 1 (MCP-1) and interleukin-10 (IL-10) levels, while suppressing tumor necrosis factor alpha (TNF-α), IL-1β, IL-6, and IL-12 levels. Mice treated with IDR-1018 at 10 mg · kg−1 of body weight had an increased survival rate in the candidemia model compared with phosphate-buffered saline (PBS)-treated mice, together with a diminished kidney fungal burden. Thus, IDR-1018 was able to protect against murine experimental candidemia and has the potential as an adjunctive therapy.
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Thisted, Louise, Mette V. Østergaard, Annemarie A. Pedersen, et al. "Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy." Scientific Reports 10, no. 1 (2020). http://dx.doi.org/10.1038/s41598-020-73046-8.
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Abstract Cardiovascular and renal complications are the predominant causes of morbidity and mortality amongst patients with diabetes. Development of novel treatments have been hampered by the lack of available animal models recapitulating the human disease. We hypothesized that experimental diabetes in rats combined with a cardiac or renal stressor, would mimic diabetic cardiomyopathy and nephropathy, respectively. Diabetes was surgically induced in male Sprague Dawley rats by 90% pancreatectomy (Px). Isoprenaline (Iso, 1 mg/kg, sc., 10 days) was administered 5 weeks after Px with the aim of inducing cardiomyopathy, and cardiac function and remodeling was assessed by echocardiography 10 weeks after surgery. Left ventricular (LV) fibrosis was quantified by Picro Sirius Red and gene expression analysis. Nephropathy was induced by Px combined with uninephrectomy (Px-UNx). Kidney function was assessed by measurement of glomerular filtration rate (GFR) and urine albumin excretion, and kidney injury was evaluated by histopathology and gene expression analysis. Px resulted in stable hyperglycemia, hypoinsulinemia, decreased C-peptide, and increased glycated hemoglobin (HbA1c) compared with sham-operated controls. Moreover, Px increased heart and LV weights and dimensions and caused a shift from α-myosin heavy chain (MHC) to β-MHC gene expression. Isoprenaline treatment, but not Px, decreased ejection fraction and induced LV fibrosis. There was no apparent interaction between Px and Iso treatment. The superimposition of Px and UNx increased GFR, indicating hyperfiltration. Compared with sham-operated controls, Px-UNx induced albuminuria and increased urine markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and podocalyxin, concomitant with upregulated renal gene expression of NGAL and kidney injury molecule 1 (KIM-1). Whereas Px and isoprenaline separately produced clinical endpoints related to diabetic cardiomyopathy, the combination of the two did not accentuate disease development. Conversely, Px in combination with UNx resulted in several clinical hallmarks of diabetic nephropathy indicative of early disease development.
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Tsujita, Maki, Nobukatsu Akita, M. Anwar Hossain, et al. "Abstract 231: ABCG1 Null and SR-BI Null Mice Reduced Plasma HDL Uptake by the Liver and Small Intestine." Arteriosclerosis, Thrombosis, and Vascular Biology 34, suppl_1 (2014). http://dx.doi.org/10.1161/atvb.34.suppl_1.231.
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Aim: To reveal cholesterol transport via non-liver excretion pathway of plasma HDL-cholesterol, we focused on small intestinal and kidney in hyper- and hypo-lipoproteinemia model mice. Method: Mouse plasma was collected within EDTA coated tubes. Plasma lipoprotein profiles were measured by size exclusion HPLC and plasma preβHDL level was detected by immno-blotting of 2D PAGE by anti-mouse apoA-I peptide polyclonal antibody. Mouse HDL was co-incubated with 3H-cholesteryl oleyl ether (CEt) presence of CETP containing human plasma proteins for 48 hrs. The (100μL) of 3H-CEt-HDL was injected trough tail vein in anesthetized mice. 30μL of blood was collected each time point to chase the radioactivity, Mice organs were harvested after 3 hrs of the injection. Since lack of cellular catabolic pathway, CEt within the cells remained. For the immunohistochemical study, mouse was anesthetized and perfused thoroughly with PBS/5mM EDTA followed by 4% PFA/0.1M PB for the fixation. Leica CM1850 Cryostat was used for sectioning (thickness 16 μm). The sections were incubated in PBS containing 5% skim milk, 0.5% Triton X-100 and 5% inactivated normal horse serum for 3 hrs at room temperature, then incubated with primary antibodies (anti-SR-BI antibody diluted to 1:10,000) for overnight at 4°C. Secondary antibodies (Alexa fluor594) dissolved in the same blocking solution were applied to the sections for 90 min at room temperature. The fluorescence samples were observed by Nikon A1RSi confocal microscopy system. Results and conclusion: HDL derived CEt in intestinal cells were significantly reduced in ABCG1 null and SR-BI null mice during this experimental period. The other hand, kidney radioactivity showed no difference. Interestingly, preβHDL in SR-BI null mice was reduced by 2D western blotting of anti-mouse apoA-I peptide. Indicates that reduced speed of the plasma apoA-I recycling in SR-BI null mice, it may also cause reduced uptake of HDL-CEt by alternative pathway. Here we show that strong SR-BI-immunoreactivity was also found in the basolateral membrane and even higher intensity in some region. SR-BI located at the basolateral membrane may function as HDL-CE receptor in the small intestine.
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Zhang, Zhiquan, Qing Ma, and Mihai V. Podgoreanu. "Abstract 13522: Annexin-A1 Bioactive Peptide Ameliorates Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI) in Rats by Upregulating the Sirtuin6/FoxO3 Pathway." Circulation 132, suppl_3 (2015). http://dx.doi.org/10.1161/circ.132.suppl_3.13522.
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Introduction: Acute kidney injury (AKI) is a prevalent and prognostically important complication of cardiac surgery. The complex multifactorial pathogenesis and lack of appropriate animal models to recapitulate the clinical insults leading to CSA-AKI have been implicated in the failure of multiple pharmacologic renoprotective strategies. We have reported anti-inflammatory and renoprotective effects of a novel Annexin-A1 (ANXA1) tripeptide (Ac-QAW) in a rodent model of experimental cardiac surgery. Here, we tested the hypothesis that Ac-QAW attenuates CSA-AKI by upregulating Sirtuin6 and Forkhead box protein O3 (SIRT6/FoxO3), key players in stress resistance, cell survival, and life span. Methods: Male Sprague-Dawley rats underwent 75 min of cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA). Animals were treated (iv) with 1 mg/kg Ac-QAW (n = 6), the commercially available ANXA1 peptide Ac2-26 (as a positive control; n = 5), or vehicle (n = 6) at 1 h before CPB, during CA, and 1 h after CPB. At 24 h post-reperfusion, renal levels of activated caspase-3, ANXA1, SIRT6, and FoxO3 were determined by Western blot; renal and plasma levels of myeloperoxidase (MPO) were determined by ELISA. Results: At 24 hours post-reperfusion following CPB/CA, rats treated with Ac-QAW showed a) reduced renal caspase-3 activity (P < 0.05); b) decreased MPO in both blood and kidney; and c) increased renal levels of ANXA1 (P < 0.05), SIRT6, and FoxO3 (P < 0.01) (Figure). Conclusions: Using a clinically relevant animal model, we provide preliminary translatable evidence that administration of Ac-QAW attenuates CSA-AKI. This may result from action by Ac-QAW to 1) reduce inflammation by increasing inflammation-resolving molecule ANXA1; 2) inhibit neutrophil transmigration; and 3) promote pro-survival mechanisms by increasing SIRT6/FoxO3 expression. More Ac-QAW studies are needed to define its exact mechanism of action and its impact on long-term functional outcomes.
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Singh, Amita, Raj Kumar, S. K. Kannaujia, Manikrishna Manikrishna, and N. P. Singh. "IMMUNOHISTOCHEMICAL STUDIES OF BLOOD BRAIN BARRIER AFTER ADMINISTRATION OF ABHRAK BHASM IN WISTAR RATS." INTERNATIONAL JOURNAL OF SCIENTIFIC RESEARCH, April 1, 2021, 13–19. http://dx.doi.org/10.36106/ijsr/6505925.
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Abhrak bhasma (AB) is a type of bhasma prepared from repeated incineration of mineral mica with decoctions of about 72 herbs. The particle size of Abhrak bhasm has been shown to be in the range of 29-88 nanometers and Fe, Ca, Si, Mg and K are found to be as major constituent. Many drugs developed to treat Central Nervous System (CNS) disorders are unable to reach the brain parenchyma in therapeutically relevant concentrations. The blood brain barrier protects brain parenchyma from the uctuation of plasma composition, from pathogenic agents and maintains homeostasis of the brain parenchyma by restricting non-specic ux of ions, peptides, proteins and even cells into and out the brain. Immunohistochemistry is being widely employed as a tool for biological studies. This study is conducted to examine the change in the continuity of Blood brain barrier by using immunohistochemistry, once Abhrak bhasm drug is given in experimental animal and also to examine the histology of organs. In this study a total of 30 adult albino Wistar rats of approximately 4 months age (approx. 150-200 gms) of either sex selected randomly to see the effect of Abhrak bhasm, an ayurvedic drug on Wistar rats. The rats were weighed, marked and divided into 5 groups each consisting of six animals. In normal control group (Group E), no drug was administered and in rest of the four treated groups (Group-A,B,C,D), Abhrak bhasm @ 36 mg/kg B.wt. was administered orally once in each rat. Brain, liver, kidneys,spleen and blood samples were collected in 10% formalin solution after euthanizing the rats at 0.5,2,6 & 12 hours of Abhrak bhasma drug intervention. The alterations in any of the biochemical parameters are within the tolerable limits of liver and kidney since the dose of abhrak bhasm did not affect liver and kidneys. In the present study, the increase in ALP level may be the result of alterations in metabolisms that occurred without any signicant alteration in histology of liver. After applying the immunohistochemistry with the research markers GFAP, CD 34, S 100, GLUT-1 and RECA-1 on the rats in groups A,B,C and D, there was no change in the intensity of immunohistochemistry, with respect to control. While on applying the Occludin, the intensity of immunohistochemistry was reduced in all the treatment groups as compared to the control group. On the basis of ndings of present study it can be concluded that the therapeutic dose of Abhrak bhasma causes changes at the level of tight junctions present in blood brain barrier in rats which is shown by immunohistochemistry with occludin research marker. There is no toxic effect of drug on different organs of rats as no signicant changes in histology of organs are seen. More studies need to be done to check the permeability of blood brain barrier for Abhrak bhasma drug, like calculating its concentration in brain tissues and other vital organs of rat.
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Ichiki, Tomoko, Gail J. Harty, Brenda K. Huntley, S. Jeson Sangaralingham, Gerald E. Harders, and John C. Burnett. "Abstract 11554: Chronic Cenderitide Administration Improves Cardiorenal Function and Remodeling in Experimental Heart Failure." Circulation 132, suppl_3 (2015). http://dx.doi.org/10.1161/circ.132.suppl_3.11554.
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Introduction: Heart failure (HF) is a major health burden in which renal impairment worsens prognosis. Targeting the vicious cycle between heart and kidney may be a more optimal therapeutic strategy for HF. The cardiac natriuretic peptides have cardiorenal protective effects through their receptor GC-A and GC-B. We sought to determine the actions of chronic administration of the dual GC-A/GC-B agonist cenderitide (CD-NP) upon cardiorenal function in experimental HF. Hypothesis: Chronic cenderitide therapy will improve cardiorenal function in HF. Methods: Experimental canine HF was induced by rapid right ventricular pacing at 240 bpm for 10 days which mimics advanced overt HF in humans. Canines (n=5 of each group) were treated with or without cenderitide (Capricor Therapeutics) subcutaneous injection (SQ) twice per day (SQ-BID, 10 ug/kg/day), cenderitide continuous SQ pump (SQ-pump, 5 ng/kg/min), or oral enalapril (ACEi, 0.5 mg/kg/day) for 10 days from the beginning of pacing. We defined hemodynamics, echo parameters, circulating neurohumoral factors at day 11, and global gene profiles using RT-PCR microarrays related to the NP system, fibrosis, growth factors, and inflammation in left atrium which undergoes early remodeling in this model. Results: The SQ-pump group showed significantly less atrial and renal weights, higher cardiac output, glomerular filtration rate, and % ejection fraction, and lower systemic vascular resistance and plasma renin activity (all p<0.05) without lowering mean arterial pressure (MAP), whereas SQ-BID and ACEi lacked these effects together with lowering MAP compared to untreated canines. Gene profile analyses showed gene related to inflammatory cytokines such as TNF-alpha, IL-1 beta, and ROCK-2, and apoptosis such as caspase 7, Fas ligand, C-Myc and TP53 were suppressed (all p<0.05) in SQ-pump but not SQ-BID or ACEi compare to un-treated group. Conclusions: Continuous SQ administration of cenderitide demonstrated superior beneficial effects on cardiorenal function and remodeling together with inhibition of circulating renin and tissue inflammatory and apoptosis pathways. Our studies suggest that continuous administration of cenderitide may provide cardiorenal protection in the setting of advanced HF.