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

Autor(es)

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]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Med, Nephrol Div, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN PHYSIOLOGY; v. 9, AUG 2 2018.
• Citações Web of Science: 4

Resumo

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)

• Processo FAPESP: 13/14204-7 - Estudo do efeito da vitamina D no modelo de fibrose renal e a participação das vias de sinalização da Wnt e do Klotho
• Beneficiário: Edgar Maquigussa
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 10/52180-4 - Fisiopatologia e regeneração das lesões renais
• Beneficiário: Nestor Schor
• Modalidade de apoio: Auxílio à Pesquisa - Temático