Podocyte apoptosis in diabetic nephropathy by BASP1 activation of the p53 pathway via WT1.

Abstract

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. BASP1 (brain acid-soluble protein) is up-regulated in podocyte-specific protein phosphatase 2A knockout mice (Pod-PP2A-KO) that develop kidney dysfunction. Here, we explore the role of BASP1 for podocytes in DN. BASP1 was assessed in kidneys from DN patients and DN mouse models, podocyte specific BASP1 knockout mice (Pod-BASP1-KO mice) were generated and studied in vivo. Furthermore, podocyte injury and apoptosis were measured after BASP1 knockdown and overexpression in a mouse podocyte cell line (MPC5). Potential signalling pathways involved in podocyte apoptosis were detected. BASP1 expression was up-regulated in DN patients compared to normal controls. BASP1 specific deletion in podocytes protected against podocyte injury by reducing the loss of expression of slit diaphragm molecules and foot process effacement in the DN model. BASP1 promoted actin cytoskeleton rearrangements and apoptosis in the MPC5 podocyte line. Molecules involved in the p53 pathway were down-regulated in BASP1 knockdown podocytes treated with high glucose compared to controls. BASP1 promoted podocyte apoptosis and P53 pathway activation through co-repression with Wilms' tumour 1 transcription factor (WT1). BASP1 activates the p53 pathway through modulation of WT1 to induce podocyte apoptosis in diabetic nephropathy.