RhoA protects the podocytes against high glucose-induced apoptosis through YAP and plays critical role in diabetic nephropathy

Abstract

Background: Podocyte apoptosis is important mechanism that leading to proteinuria in Diabetic nephropathy (DN), but the underling mechanisms that cause podocyte apoptosis in DN are not very clear. We have recently demonstrated that RhoA, a small GTPase protein, effectively protected podocyte apoptosis induced by LPS and ADR in vitro. However, the potential role of RhoA in DN is unknown.

Methods and results: Conditionally immortalized mouse podocyte cells, C57BL/KsJ, db/db diabetic mice, and renal biopsies from patients with DN were used for study. The treatment of podocytes with high glucose (HG) for 48h significantly induced cell apoptosis and decreased RhoA expression and its activity. The expression of RhoA was also decreased in glomerular podocytes of db/db mice and patients with DN. Knockdown of RhoA by siRNA contributed in the apoptosis of podocyte and induced proteinuria in db/db mice. Beyond the increased pro-apoptotic Bax and the decreased anti-apoptotic Bcl-2, RhoA knockdown also inhibited the expression of a nuclear protein of YAP in podocyte. Over expression active form of YAP completely abolished the apoptosis of podocyte induced by RhoA knockdown.

Conclusion: RhoA plays a critical role in DN probably by mediating the podocyte apoptosis through YAP. RhoA may be a novel molecular target for the treatment of DN.

Keywords: Diabetic nephropathy; Podocyte apoptosis; RhoA; YAP.