Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases

Abstract

Background Dipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear. Methods The localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte. Results DPP-4 activity under normal conditions was observed in some Bowman's capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA. Saxagliptin also improved the detachment of podocytes. Conclusions DPP-4 activity induces degradation of synaptopodin and reduction of RhoA, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.

The role and mechanism of the gut microbiota in the development and treatment of diabetic kidney disease

“…DPP-4 inhibitors can increase the level of GLP-1 and GLP-2 by inhibiting DPP-4 (Ning et al, 2020;Yan et al, 2016). Studies have confirmed that DPP-4 inhibitors exhibit renoprotective effects via inhibiting inflammation and oxidative stress, preventing podocyte injury, and delaying glomerulosclerosis in DKD (Kawanami et al, 2021;Kubo et al, 2020;Mima, 2022). Sitagliptin, a DPP-4 inhibitor, was reported to regulate the dysbiosis of gut microbiota in a rat model of diabetes, and the potential beneficial effect may be related to GLP-2 (Yan et al, 2016).…”