There is no doubt that rates of chronic kidney disease are escalating and that this rise is the main contributor to the increasing prevalence of diabetic nephropathy. It is also clear that the increase in kidney failure continues despite tight blood glucose and blood pressure control, as well as renin-angiotensin system blockade. In response, research into novel therapies to treat diabetic nephropathy is expanding, but to date nothing has translated into clinical use. The dipeptidyl peptidase-4 (DPP-4) inhibitors are oral, weight-neutral hypoglycemic drugs used to treat patients with type 2 diabetes. DPP-4 cleaves polypeptides with a proline/alanine in the penultimate position at the amino-terminal position. Hence, the net physiologic effect is a complex interplay between the resulting substrate/product profile in a particular disease milieu (rather than a specific signaling pathway). Cleaved substrates may either be activated, inactivated, or bear no functional relevance. DPP-4 inhibitors lower blood glucose levels by raising the half-life of short-lived endogenous incretins, such as GLP-1 and glucose-dependent insulinotropic polypeptide. However, the ability of DPP-4 to cleave a host of additional membrane-bound substrates that exert nonenzymatic properties by interacting or colocalizing with other membrane proteins/receptors suggests it may be a novel and …