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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Maquigussa, Edgar [1] ; Patemo, Josne C. [1] ; de Oliveira Pokorny, Gabriel H. [1] ; Perez, Mariana da Silva [1] ; Varela, Vanessa A. [1] ; Novaes, Antonio da Silva [1] ; Schor, Nestor [1] ; Boim, Mirian A. [1]
Total Authors: 8
Affiliation:
[1] Univ Fed Sao Paulo, Dept Med, Nephrol Div, Sao Paulo - Brazil
Total Affiliations: 1
Document type: Journal article
Source: FRONTIERS IN PHYSIOLOGY; v. 9, AUG 2 2018.
Web of Science Citations: 4
Abstract

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 gamma (PPAR-gamma), and the Wnt/beta-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-gamma, 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-beta in the remnant kidney. The anti-fibrotic Klotho and PPAR-gamma 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-gamma 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-gamma, and suppressed by BADGE, an antagonist of PPAR-gamma, suggesting that the effect of Ang II downregulating klotho is mediated by PPAR-gamma. These data suggest that activation of the Wnt pathway together with downregulation of PPAR-gamma that in turn suppresses klotho contribute to potentiating the profibrotic effect of Ang II. (AU)