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Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the re...

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Autores principales: Suh, Sang Heon, Choi, Hong Sang, Kim, Chang Seong, Kim, In Jin, Ma, Seong Kwon, Scholey, James W., Kim, Soo Wan, Bae, Eun Hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695622/
https://www.ncbi.nlm.nih.gov/pubmed/31390839
http://dx.doi.org/10.3390/ijms20153843
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author Suh, Sang Heon
Choi, Hong Sang
Kim, Chang Seong
Kim, In Jin
Ma, Seong Kwon
Scholey, James W.
Kim, Soo Wan
Bae, Eun Hui
author_facet Suh, Sang Heon
Choi, Hong Sang
Kim, Chang Seong
Kim, In Jin
Ma, Seong Kwon
Scholey, James W.
Kim, Soo Wan
Bae, Eun Hui
author_sort Suh, Sang Heon
collection PubMed
description Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin–angiotensin system (RAS) and transforming growth factor β (TGFβ) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3(–/–) mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3(–/–) mice by olmesartan treatment. Upregulation of TGFβ and activation of its downstream in Col4a3(–/–) mice were attenuated by olmesartan in Col4a3(–/–) mice. Intriguingly, TGFβ expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3(–/–) mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3(–/–) mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFβ-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFβ feedback loop to counterbalance intrarenal RAS activation.
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spelling pubmed-66956222019-09-05 Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ Suh, Sang Heon Choi, Hong Sang Kim, Chang Seong Kim, In Jin Ma, Seong Kwon Scholey, James W. Kim, Soo Wan Bae, Eun Hui Int J Mol Sci Article Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin–angiotensin system (RAS) and transforming growth factor β (TGFβ) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3(–/–) mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3(–/–) mice by olmesartan treatment. Upregulation of TGFβ and activation of its downstream in Col4a3(–/–) mice were attenuated by olmesartan in Col4a3(–/–) mice. Intriguingly, TGFβ expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3(–/–) mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3(–/–) mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFβ-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFβ feedback loop to counterbalance intrarenal RAS activation. MDPI 2019-08-06 /pmc/articles/PMC6695622/ /pubmed/31390839 http://dx.doi.org/10.3390/ijms20153843 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Suh, Sang Heon
Choi, Hong Sang
Kim, Chang Seong
Kim, In Jin
Ma, Seong Kwon
Scholey, James W.
Kim, Soo Wan
Bae, Eun Hui
Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ
title Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ
title_full Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ
title_fullStr Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ
title_full_unstemmed Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ
title_short Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ
title_sort olmesartan attenuates kidney fibrosis in a murine model of alport syndrome by suppressing tubular expression of tgfβ
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695622/
https://www.ncbi.nlm.nih.gov/pubmed/31390839
http://dx.doi.org/10.3390/ijms20153843
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