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Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1

BACKGROUND: Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability,...

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Autores principales: Peng, Hui, Luo, Pengli, Li, Yuanqing, Wang, Cheng, Liu, Xun, Ye, Zengchun, Li, Canming, Lou, Tanqi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828237/
https://www.ncbi.nlm.nih.gov/pubmed/24244596
http://dx.doi.org/10.1371/journal.pone.0080009
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author Peng, Hui
Luo, Pengli
Li, Yuanqing
Wang, Cheng
Liu, Xun
Ye, Zengchun
Li, Canming
Lou, Tanqi
author_facet Peng, Hui
Luo, Pengli
Li, Yuanqing
Wang, Cheng
Liu, Xun
Ye, Zengchun
Li, Canming
Lou, Tanqi
author_sort Peng, Hui
collection PubMed
description BACKGROUND: Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN. METHODS: We assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice. RESULTS: High glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN. CONCLUSION: Our results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN.
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spelling pubmed-38282372013-11-16 Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1 Peng, Hui Luo, Pengli Li, Yuanqing Wang, Cheng Liu, Xun Ye, Zengchun Li, Canming Lou, Tanqi PLoS One Research Article BACKGROUND: Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN. METHODS: We assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice. RESULTS: High glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN. CONCLUSION: Our results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN. Public Library of Science 2013-11-14 /pmc/articles/PMC3828237/ /pubmed/24244596 http://dx.doi.org/10.1371/journal.pone.0080009 Text en © 2013 Peng et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Peng, Hui
Luo, Pengli
Li, Yuanqing
Wang, Cheng
Liu, Xun
Ye, Zengchun
Li, Canming
Lou, Tanqi
Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1
title Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1
title_full Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1
title_fullStr Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1
title_full_unstemmed Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1
title_short Simvastatin Alleviates Hyperpermeability of Glomerular Endothelial Cells in Early-Stage Diabetic Nephropathy by Inhibition of RhoA/ROCK1
title_sort simvastatin alleviates hyperpermeability of glomerular endothelial cells in early-stage diabetic nephropathy by inhibition of rhoa/rock1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828237/
https://www.ncbi.nlm.nih.gov/pubmed/24244596
http://dx.doi.org/10.1371/journal.pone.0080009
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