The activation of the(Pro)renin receptor (PRR) stimulates fibrotic factors expression independent of b‐catenin signaling pathway in collecting duct cells

Abstract

Binding of the PRR to renin and prorenin activates intracellular signals independent of angiotensin II. The PRR is a component of the Wnt signaling pathway working as an adaptor between Wnt receptor and the vacuolar H+‐ATPase. The expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals; however its role in renal damage remains unclear. In this study we tested the hypothesis that the PRR activation induces the expression of fibronectin and collagen I via the b‐catenin pathway in mouse collecting duct M‐1 cells. Human recombinant prorenin (hrPR) for 16 h in M‐1 cells increased the mRNA and protein levels of fibronectin (1.48±0.1 fold change), collagen I (1.53±0.1 fold‐change) as well as the b‐catenin target genes, cyclin D1 (1.9 ± 0.1 fold change) and c‐myc (2.1 ± 0.2 fold change). Inhibition of b‐catenin degradation with pyrvinium pamoate (10‐9 M) did not prevent the hrPR‐induced expression of all these genes. However, when the cells were transfected with a siRNA‐PRR, the hrPR‐dependent increases in fibronectin, collagen, cyclin D1 and c‐myc were prevented. Furthermore, hrPR treatment did not change the stationary protein level of β‐catenin or phosphorylation of GSK‐3β until 24h, but the level of pERK1/2 displayed a significant increase after 8h of treatment (2.9 ± 0.21 fold change, P<0.05).These results indicate that in collecting duct cells, PRR activation stimulates fibrotic genes independent of β‐catenin pathway.