A dipeptidyl peptidase inhibitor, evogliptin, directly prevents nephrin loss and podocyte damage via post-transcriptional regulation

Background: Loss of podocytes due to podocyte damage leads to impairment of renal filtration function, thereby bringing about proteinuria in glomerular diseases. Dipeptidyl peptidase 4 (DPP4) inhibitors are reported to protect against podocyte damage in preclinical animal models. However, the direct effects of DPP4 inhibitors on podocytes are not yet fully understood. Methods: Streptozotocin-induced diabetic mice and db/db mice were provided with evogliptin, linagliptin, or irbesartan for 12 weeks. Mouse and human podocytes were treated for 72 h and cell lysate and medium were analyzed. Results: In diabetic mice with renal impairment, evogliptin treatment was more efficacious than linagliptin in blocking urinary nephrin excretion, with preserved renal nephrin and phospho-nephrin levels observed regardless of glucose control. In differentiated murine podocytes and primary human podocytes, evogliptin also outperformed linagliptin in preserving nephrin protein levels under high glucose and angiotensin II conditions that mimicked diabetic nephropathy conditions. Intriguingly, after 72 h of treatment, evogliptin effectively blocked the increase in cellular DPP4 activity without altering DPP4 expression levels, while linagliptin did not. Blocking protein synthesis or clathrin-mediated endocytosis eliminated the nephrin-preserving effects of evogliptin, but nephrin gene expression was not altered by any treatments, suggesting potential post-transcriptional regulation. In podocytes, evogliptin directly reduced the stress-induced cellular signals, pro-apoptotic protein cleavage and shedding of membrane DPP4 that increased under diabetic nephropathy-mimicking conditions. Conclusions: Our findings suggest a direct protective effect of evogliptin against podocyte damage through maintenance of nephrin levels, alleviation of stress responses and a reduction in apoptotic cell death.