Chapter 5 Inhibition of the serine exopeptidase DPP-IV as a means of mitigation of diabetic nephropathy

Diabetic nephropathy (DN) is a serious consequence of diabetes that leads to chronic kidney disease (CKD), end stage renal disease (ESRD), and cardiovascular damage. It is recognized as a major microvascular complication of diabetes which is characterized by increase in urine albumin excretion (albuminuria), glomerular lesions along with tubulointerstitial lesions, and tubular atrophy and decline in glomerular filtration rate (GFR). Current treatment regimen for DN targets regulation of high blood glucose and hypertension. Dipeptidyl peptidase-IV (DPP-IV) inhibitors (gliptins) are a major class of antidiabetic medications which cover almost 50% of the market distribution of the oral hypoglycemic medicines. The serine exopeptidase, DPP-IV or adenosine deaminase complexing protein 2 or CD26, is a form of transmembrane type II glycoprotein, expressed in different cell types including smooth muscles, adipocytes, endothelial cells, renal proximal tubular cells, and podocytes. DPP-IV enzyme rapidly cleaves and inactivates incretins like glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP). Incretins, released from enteroendocrine cells, enhance insulin secretion and decrease glucagon levels. DPP-IV inhibitors increase the levels of active GLP-1 and GIP by inhibiting DPP-IV enzymatic activity and improve hyperglycaemic conditions. Since the introduction of sitagliptin in 2006, as the first DPP-IV inhibitors, a number of such gliptins have been in picture including saxagliptin, linagliptin, and alogliptin (US, FDA) and anagliptin, teneligliptin, trelagliptin, and omarigliptin (approved in Japan). Many of these DPP-IV inhibitors have also been in use along with metformin. Unfortunately, these drugs can slow the process but do not prevent disease progression and physical and financial costs associated with the disease. Long-term safety, prognosis, and bioavailability are also questionable while using these synthetic leads. Therefore, there has been a pressing need for novel and potent natural therapeutic agents that are effective with fewer or no side effects. Extensive search is going on to evaluate the properties of medicinal plants and their phytocompounds as potent DPP-IV inhibitors. Numerous plant-derived phytocompounds like alkaloids, flavonoids, terpenoids, phenols, and glycosides are reported to be inhibitors of DPP-IV. Berberine, resveratrol, luteolin, quercetin, coumarin, galangin, apigenin, naringenin, and so on are proved to be highly effective DPP-IV inhibitors. This chapter highlights latest research on the role of bioactive compounds or natural plant derived products as alternative to available synthetic DPP-IV inhibitors. The article also summarizes the important molecular mechanisms involved to expand this research area for potential draggability.