RhoA/ROCK inhibition attenuates endothelin-1-induced glomerulopathy in the rats.

Autor: Saleh MA; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: mohamed.saleh@sharjah.ac.ae., Shaaban AA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City 35712, Egypt., Talaat IM; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Pathology Department, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt., Elmougy A; Pediatric Nephrology Unit, Mansoura University Children's Hospital, Mansoura University, Mansoura 35516, Egypt., Adra SF; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates., Ahmad F; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi 59911, United Arab Emirates., Qaisar R; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates., Elmoselhi AB; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates., Abu-Gharbieh E; Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates., El-Huneidi W; Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates., Eladl MA; Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates., Shehatou G; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City 35712, Egypt., Kafl HE; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2023 Jun 15; Vol. 323, pp. 121687. Date of Electronic Publication: 2023 Apr 06.
DOI: 10.1016/j.lfs.2023.121687
Abstrakt: Endothelin-1 (ET-1) contributes to the development of kidney diseases. However, the underlying molecular mechanism is largely undefined. Here we sought to investigate the potential role of ET-1 receptors, ET A and ET B in the regulation of increased glomerular permeability and underlying signaling pathways post-ET-1 infusion. Male Sprague-Dawley rats were infused with ET-1 (2 pmol/kg per minute, i.v.) for four weeks, and the effect on glomerular permeability to albumin (P alb ) and albuminuria was measured. The selective ROCK-1/2 inhibitor, Y-27632, was administered to a separate group of rats to determine its effect on ET-1-induced P alb and albuminuria. The role of ET A and ET B receptors in regulating RhoA/ROCK activity was determined by incubating isolated glomeruli from normal rats with ET-1 and with selective ET A and ET B receptor antagonists. ET-1 infusion for four weeks significantly elevated P alb and albuminuria. Y-27632 significantly reduced the elevation of P alb and albuminuria. The activities of both RhoA and ROCK-1/2 were increased by ET-1 infusion. Selective ET B receptor antagonism had no effect on the elevated activity of both RhoA and ROCK-1/2 enzymes. Selective ET A receptor and combined ET A /ET B receptors blockade restored the activity of RhoA and ROCK-1/2 to normal levels. In addition, chronic ET-1 infusion increased the levels of glomerular inflammatory and fibrotic markers. These effects were all attenuated in rats following ROCK-1/2 inhibition. These observations suggest that ET-1 contributes to increased albuminuria, inflammation, and fibrosis by modulating the activity of the ET A -RhoA/ROCK-1/2 pathway. Selective ET A receptor blockade may represent a potential therapeutic strategy to limit glomerular injury and albuminuria in kidney disease.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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