The Effects of Losartan on Expressions of Klotho and Wnt in the 5/6 Nephrectomy Model of Progressive Chronic Kidney Disease

Abstract

Klotho is a transmembrane protein expressed in different tissues but in particularly high levels in the kidney. Soluble klotho acts an endocrine factor with diverse functions including endothelium protection and reducing inflammation and fibrosis through mechanisms involving Wnt and TGFbeta1 signaling. Renal fibrosis is the end stage of the progressive chronic kidney disease (CKD) and renal klotho is markedly decreased in CKD patients. Renin angiotensin system (RAS) blockade is a relevant therapy to reduce CKD progression since it has a pivotal role in renal fibrogenesis. We investigated the effects of losartan on Klotho/Wnt signaling in 5/6 nephrectomy model of CKD in rats. Adult male Wistar rats underwent 5/6 nephrectomy (NX) were separated into 2 groups, NX control and NX treated with losartan (LOS, 25 mg/kg) in the drinking water from day 1 after nephrectomy. Blood pressure (MAP) was measured weekly. Urine was colected to determine proteinuria. After 8 weeks, rats were sacrificed and the remmnant kidney was removed and prepared to estimate the renal expression of collagen, epithelial‐to‐mesenchymal transition (EMT) marker (FSP1) and Klotho signaling (Klotho, Wnt and GSK3β) by real time PCR. NX rats presented hypertension and proteinuria that were blunted by LOS treatment. LOS also induced a reduction in the expression of the fibrosis markers collagen and FSP1. Klotho was reduced in NX animals and LOS significantly increased the expression. The LOS treatment increased Wnt3 expression and did not change the Wnt7b and GSK3β. These data suggest that besides the reduction in the MAP, the benefical renal effect of losartan may be at least in part due to upregulation of klotho expression.