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Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity

Protease‐activated receptors (PAR) play an important role in the regulation of cellular function by the coagulation system, and they are activated by thrombin. PAR‐1 is expressed in both endothelial cells and podocytes in the kidney. The role of PAR1 in the maintenance of the glomerular filtration b...

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Autores principales: Medipally, Ajay, Xiao, Min, Biederman, Laura, Satoskar, Anjali A., Ivanov, Iouri, Rovin, Brad, Parikh, Samir, Kerlin, Bryce A., Brodsky, Sergey V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9349585/
https://www.ncbi.nlm.nih.gov/pubmed/35923090
http://dx.doi.org/10.14814/phy2.15343
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author Medipally, Ajay
Xiao, Min
Biederman, Laura
Satoskar, Anjali A.
Ivanov, Iouri
Rovin, Brad
Parikh, Samir
Kerlin, Bryce A.
Brodsky, Sergey V.
author_facet Medipally, Ajay
Xiao, Min
Biederman, Laura
Satoskar, Anjali A.
Ivanov, Iouri
Rovin, Brad
Parikh, Samir
Kerlin, Bryce A.
Brodsky, Sergey V.
author_sort Medipally, Ajay
collection PubMed
description Protease‐activated receptors (PAR) play an important role in the regulation of cellular function by the coagulation system, and they are activated by thrombin. PAR‐1 is expressed in both endothelial cells and podocytes in the kidney. The role of PAR1 in the maintenance of the glomerular filtration barrier is not clear. Anticoagulant‐related nephropathy (ARN) is a kidney disease with glomerular hematuria and red blood cell tubular casts. We validated 5/6 nephrectomy (5/6NE) in rats as a model of ARN and had demonstrated that direct thrombin inhibitor (dabigatran) induces ARN. The aim of this study was to investigate the role of PAR‐1 in the ARN pathogenesis. 5/6NE rats were treated with dabigatran (150 mg/kg/day), PAR‐1 inhibitor SCH79797 (1 and 3 mg/kg/day) and PAR‐1 agonist TFLLR‐NH2 (0.25 and 0.50 µmol/kg/day) for 7 days. Serum creatinine and hematuria were assessed daily. Kidney morphology was evaluated at the end of the study. In 5/6NE rats treated with either dabigatran or combination with a PAR‐1 modulator, there was an elevation in serum creatinine, glomerular hematuria, red blood casts in the tubules, and acute tubular epithelial cell injury. Interestingly, both PAR‐1 modulators in a dose‐depended manner had similar effects on the serum creatinine levels and hematuria as those of dabigatran. Dabigatran‐induced increase in the systolic blood pressure was not affected by PAR‐1 modulators. In conclusion, the normal function of PAR‐1 is crucial to maintain the glomerular filtration barrier integrity. Either activation or blockage of PAR‐1 leads to glomerular hematuria and subsequent acute tubular epithelial cell injury.
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spelling pubmed-93495852022-08-09 Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity Medipally, Ajay Xiao, Min Biederman, Laura Satoskar, Anjali A. Ivanov, Iouri Rovin, Brad Parikh, Samir Kerlin, Bryce A. Brodsky, Sergey V. Physiol Rep Original Articles Protease‐activated receptors (PAR) play an important role in the regulation of cellular function by the coagulation system, and they are activated by thrombin. PAR‐1 is expressed in both endothelial cells and podocytes in the kidney. The role of PAR1 in the maintenance of the glomerular filtration barrier is not clear. Anticoagulant‐related nephropathy (ARN) is a kidney disease with glomerular hematuria and red blood cell tubular casts. We validated 5/6 nephrectomy (5/6NE) in rats as a model of ARN and had demonstrated that direct thrombin inhibitor (dabigatran) induces ARN. The aim of this study was to investigate the role of PAR‐1 in the ARN pathogenesis. 5/6NE rats were treated with dabigatran (150 mg/kg/day), PAR‐1 inhibitor SCH79797 (1 and 3 mg/kg/day) and PAR‐1 agonist TFLLR‐NH2 (0.25 and 0.50 µmol/kg/day) for 7 days. Serum creatinine and hematuria were assessed daily. Kidney morphology was evaluated at the end of the study. In 5/6NE rats treated with either dabigatran or combination with a PAR‐1 modulator, there was an elevation in serum creatinine, glomerular hematuria, red blood casts in the tubules, and acute tubular epithelial cell injury. Interestingly, both PAR‐1 modulators in a dose‐depended manner had similar effects on the serum creatinine levels and hematuria as those of dabigatran. Dabigatran‐induced increase in the systolic blood pressure was not affected by PAR‐1 modulators. In conclusion, the normal function of PAR‐1 is crucial to maintain the glomerular filtration barrier integrity. Either activation or blockage of PAR‐1 leads to glomerular hematuria and subsequent acute tubular epithelial cell injury. John Wiley and Sons Inc. 2022-08-03 /pmc/articles/PMC9349585/ /pubmed/35923090 http://dx.doi.org/10.14814/phy2.15343 Text en © 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Medipally, Ajay
Xiao, Min
Biederman, Laura
Satoskar, Anjali A.
Ivanov, Iouri
Rovin, Brad
Parikh, Samir
Kerlin, Bryce A.
Brodsky, Sergey V.
Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity
title Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity
title_full Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity
title_fullStr Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity
title_full_unstemmed Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity
title_short Role of protease‐activated receptor‐1 (PAR‐1) in the glomerular filtration barrier integrity
title_sort role of protease‐activated receptor‐1 (par‐1) in the glomerular filtration barrier integrity
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9349585/
https://www.ncbi.nlm.nih.gov/pubmed/35923090
http://dx.doi.org/10.14814/phy2.15343
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