More than just an enzyme: Dipeptidyl peptidase-4 (DPP-4) and its association with diabetic kidney remodelling

Purpose of the review: This review article discusses recent advances in the mechanism of dipeptidyl peptidase-4 (DPP-4) actions in renal diseases, especially diabetic kidney fibrosis, and summarizes anti-fibrotic functions of various DPP-4 inhibitors in diabetic nephropathy (DN). Recent findings: DN is a common complication of diabetes and is a leading cause of the end-stage renal disease (ESRD). DPP-4 is a member of serine proteases, and more than 30 substrates have been identified that act via several biochemical messengers in a variety of tissues including kidney. Intriguingly, DPP-4 actions on the diabetic kidney is a complex mechanism, and a variety of pathways are involved including increasing GLP-1/SDF-1, disrupting AGE-RAGE pathways, and integrin-beta- and TGF-beta-Smad-mediated signalling pathways that finally lead to endothelial to mesenchymal transition. Interestingly, an array of DPP-4 inhibitors is well recognized as oral drugs to treat type 2 diabetic (T2D) patients, which promote better glycemic control. Furthermore, recent experimental and preclinical data reveal that DPP-4 inhibitors may also exhibit protective effects in renal disease progression including anti-fibrotic effects in the diabetic kidney by attenuating above signalling cascade(s), either singly or as a combinatorial effect. In this review, we discussed the anti-fibrotic effects of DPP-4 inhibitors based on recent reports along with the possible mechanism of actions and future perspectives to underscore the beneficial effects of DPP-4 inhibitors in DN. Summary: With recent experimental, preclinical, and clinical evidence, we summarized DPP-4 activities and its mechanism of actions in diabetic kidney diseases. A knowledge gap of DPP-4 inhibition in controlling renal fibrosis in DN has also been postulated in this review for future research perspectives.