SP191Protective effects of Saxagliptin on podocyte injury

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INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) is a serine protease and inhibits the degradation of glucagon-like peptide 1 (GLP-1) function. Thus, its inhibitors are used worldwide for treating type 2 diabetes mellitus. The pleiotropic effects of DPP-4 inhibitors has recently discussed such as anti-oxidant, anti-inflammatory, and anti-fibrotic effects. DPP-4 inhibitors have beneficial effect to improve albuminuria and reduce renal injury including glomerular damage independent of hypoglycemic effect. Although DPP-4 is mainly expressed in kidney, physiological function of DPP-4 remains still obscure. METHODS: Present study clarified localization of renal DPP-4 activity in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and effect of DPP-4 inhibitor in human cultured podocyte. RESULTS: DPP-4 activity under normal conditions was observed in some Bowman's capsular epithelial cells and proximal tubule, but not in glomerulus. DPP-4 activities was present in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesion in diabetic nephropathy and a partial podocytes in focal segmental glomerulosclerosis. Of note, one of the DPP-4 inhibitor, saxagliptin, suppressed DPP-4 activities in podocytes and proximal tubules. To assess the effect of DPP-4 inhibitor on podocyte, we focused on human cultured podocyte injured by Adriamycin. Adriamycin induced podocytes injuries with increase of DPP-4 activity and this activity was suppressed by saxagliptin dose dependently. In damaged podocyte, synaptopodin which is associated cytoskelton was degraded. Treatment with saxagliptin maintained structure of synaptopodin, RhoA and improved detachment of podocyte. CONCLUSIONS: These results indicate that DPP-4 activity induces degradation of synaptopodin, resulting in destruction of podocyte cytoskeleton. Saxagliptin may have a pleiotropic effects to prevent podocyte injury.

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