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

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 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.

Renoprotective effect of irbesartan in a rat model of gentamicin-induced nephrotoxicity: Role of oxidative stress

“…confirmed the antioxidant effect of RAS blockers such as losartan which leads to significant renoprotective effect during ischemic renal injury. [21]…”

αKlotho attenuates cardiac hypertrophy and increases myocardial fibroblast growth factor 21 expression in uremic rats

“…Protein bands were visualized using the Immobilon Western HRP substrate (Millipore), and quantified using Uvitec analyses software (Uvitec Limited, Cambridge, UK) as previously described. 42 Ponceau staining was used as a loading control as previously described. 43…”

Lipid Accumulation and Chronic Kidney Disease

“…In a randomized, double blind, placebo-controlled study, 8-weeks treatment of rosiglitazone in CKD subjects lowered the homoeostasis model assessment (HOMA) score and high-sensitivity C-reactive protein (hs-CRP), indicating an increased insulin sensitivity in patients with CKD treated with rosiglitazone [102]. The inhibition of the Wnt signaling-mediated fibrogenesis may represent another mechanism of kidney protection by PPARγ activation [103,104]. Moreover, PPARγ also participates in the regulation of antioxidant production, including superoxide dismutase 2 and glutathione peroxidase 1, which play important roles in metabolic disorders and progression of CKD [105].…”