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Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model

Renin angiotensin system (RAS) blockade reduces the progression of chronic kidney disease (CKD) independently of its antihypertensive effect. Ang II-induced fibrosis can be mediated by molecules such as klotho, peroxisome proliferator-activate receptor γ (PPAR-γ), and the Wnt/β-catenin pathway; howe...

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Autores principales: Maquigussa, Edgar, Paterno, Josne C., de Oliveira Pokorny, Gabriel H., da Silva Perez, Mariana, Varela, Vanessa A., da Silva Novaes, Antônio, Schor, Nestor, Boim, Mirian A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084001/
https://www.ncbi.nlm.nih.gov/pubmed/30116202
http://dx.doi.org/10.3389/fphys.2018.01033
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author Maquigussa, Edgar
Paterno, Josne C.
de Oliveira Pokorny, Gabriel H.
da Silva Perez, Mariana
Varela, Vanessa A.
da Silva Novaes, Antônio
Schor, Nestor
Boim, Mirian A.
author_facet Maquigussa, Edgar
Paterno, Josne C.
de Oliveira Pokorny, Gabriel H.
da Silva Perez, Mariana
Varela, Vanessa A.
da Silva Novaes, Antônio
Schor, Nestor
Boim, Mirian A.
author_sort Maquigussa, Edgar
collection PubMed
description Renin angiotensin system (RAS) blockade reduces the progression of chronic kidney disease (CKD) independently of its antihypertensive effect. Ang II-induced fibrosis can be mediated by molecules such as klotho, peroxisome proliferator-activate receptor γ (PPAR-γ), and the Wnt/β-catenin pathway; however, the interaction among these molecules and RAS activation is not completely known. The aim of this study was to investigate a possible link between RAS, PPAR-γ, and Klotho in the 5/6 nephrectomy (NX) animals. NX rats presented hypertension that was blunted by both losartan and propranolol, however, only losartan was able to reduce the expression levels of fibronectin FSP1 and TGF-β in the remnant kidney. The anti-fibrotic Klotho and PPAR-γ were reduced in the remnant kidney, and losartan, but not propranolol, restored their levels. In contrast, the profibrotic Wnt 7a and Wnt 3 were upregulated and losartan prevented the increase in Wnts. In vitro, Ang II induced a decrease in both klotho and in PPAR-γ in Madin-Darby canine kidney (MDCK) cells, and this effect was blunted by losartan. However, klotho expression was increased by pioglitazone, an agonist of PPAR-γ, and suppressed by BADGE, an antagonist of PPAR-γ, suggesting that the effect of Ang II downregulating klotho is mediated by PPAR-γ. These data suggest that activation of the Wnt pathway together with downregulation of PPAR-γ that in turn suppresses klotho contribute to potentiating the profibrotic effect of Ang II.
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spelling pubmed-60840012018-08-16 Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model Maquigussa, Edgar Paterno, Josne C. de Oliveira Pokorny, Gabriel H. da Silva Perez, Mariana Varela, Vanessa A. da Silva Novaes, Antônio Schor, Nestor Boim, Mirian A. Front Physiol Physiology Renin angiotensin system (RAS) blockade reduces the progression of chronic kidney disease (CKD) independently of its antihypertensive effect. Ang II-induced fibrosis can be mediated by molecules such as klotho, peroxisome proliferator-activate receptor γ (PPAR-γ), and the Wnt/β-catenin pathway; however, the interaction among these molecules and RAS activation is not completely known. The aim of this study was to investigate a possible link between RAS, PPAR-γ, and Klotho in the 5/6 nephrectomy (NX) animals. NX rats presented hypertension that was blunted by both losartan and propranolol, however, only losartan was able to reduce the expression levels of fibronectin FSP1 and TGF-β in the remnant kidney. The anti-fibrotic Klotho and PPAR-γ were reduced in the remnant kidney, and losartan, but not propranolol, restored their levels. In contrast, the profibrotic Wnt 7a and Wnt 3 were upregulated and losartan prevented the increase in Wnts. In vitro, Ang II induced a decrease in both klotho and in PPAR-γ in Madin-Darby canine kidney (MDCK) cells, and this effect was blunted by losartan. However, klotho expression was increased by pioglitazone, an agonist of PPAR-γ, and suppressed by BADGE, an antagonist of PPAR-γ, suggesting that the effect of Ang II downregulating klotho is mediated by PPAR-γ. These data suggest that activation of the Wnt pathway together with downregulation of PPAR-γ that in turn suppresses klotho contribute to potentiating the profibrotic effect of Ang II. Frontiers Media S.A. 2018-08-02 /pmc/articles/PMC6084001/ /pubmed/30116202 http://dx.doi.org/10.3389/fphys.2018.01033 Text en Copyright © 2018 Maquigussa, Paterno, Pokorny, Perez, Varela, Novaes, Schor and Boim. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Maquigussa, Edgar
Paterno, Josne C.
de Oliveira Pokorny, Gabriel H.
da Silva Perez, Mariana
Varela, Vanessa A.
da Silva Novaes, Antônio
Schor, Nestor
Boim, Mirian A.
Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model
title Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model
title_full Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model
title_fullStr Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model
title_full_unstemmed Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model
title_short Klotho and PPAR Gamma Activation Mediate the Renoprotective Effect of Losartan in the 5/6 Nephrectomy Model
title_sort klotho and ppar gamma activation mediate the renoprotective effect of losartan in the 5/6 nephrectomy model
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084001/
https://www.ncbi.nlm.nih.gov/pubmed/30116202
http://dx.doi.org/10.3389/fphys.2018.01033
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