Mechanisms and pathways of anti‐inflammatory activity of DPP‐4 inhibitors in cardiovascular and renal protection

Abstract

Dipeptidyl peptidase-4 (DPP-4) cleaves N-terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP-4 expression and activity. Besides the regulation of glucose metabolism, DPP-4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP-4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti-inflammatory activity of clinically used DPP-4 inhibitors in cardiovascular and renal protection.

An Overview, Advantages and Therapeutic Potential of Nonpeptide Positive Allosteric Modulators of Glucagon‐Like Peptide‐1 Receptor

“…The earliest strategy to increase endogenous levels of GLP‐1 has been the use of DPP‐4 inhibitors, which we have recently reviewed . Indications are that DPP‐4 inhibitors are most likely go beyond type 2 diabetes treatment because they show beneficial effects in repair after myocardial infarction, as well as in cardiovascular and renal protection . The development of DPP‐4 inhibitors has been followed by the development of peptide agonists of GLP‐1R that are resistant to DPP‐4 inactivation, such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and taspoglutide.…”

“…[10] Indicationsa re that DPP-4 inhibitors are most likely go beyond type 2d iabetes treatment because they show beneficial effects in repair after myocardial infarction, [11] as well as in cardiovascular and renal protection. [12] The development of DPP-4 inhibitors has been followed by the development of peptide agonists of GLP-1Rt hat are resistantt o DPP-4 inactivation, such as exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and taspoglutide. These peptides, however,r equire parenteral administration due to inherent in-stabilityi nt he proteolytic milieu of the gastrointestinal tract, [8,9,13] and adherence to an injectable medication might be the limiting factor in life-long therapy.U nfortunately,t argeting the GLP-1Ro rthosteric binding site with direct small-molecule drugs would requiret heir interference with protein-protein interactions, whichs eldom leads to successful drug-discovery campaigns; [14] this opens aw indow for the development of orally available small-molecule GLP-1R allostericm odulators.…”

Treatment options for type 2 diabetes mellitus in patients with chronic kidney disease – old and new drugs

“…Evidence is emerging suggesting that these drugs may have renoprotective effects unrelated to their antihyperglycemic action 33,34 . Several renal beneficial effects have been described in animal models of diabetic and non -diabetic nephropathy, human cell lines and even in human studies for all DPP -4 inhibitors available 34 .…”

“…Evidence is emerging suggesting that these drugs may have renoprotective effects unrelated to their antihyperglycemic action 33,34 . Several renal beneficial effects have been described in animal models of diabetic and non -diabetic nephropathy, human cell lines and even in human studies for all DPP -4 inhibitors available 34 . These include anti -oxidative and anti -inflammatory actions, decreased podocyte loss, decreased albuminuria, decreased tubular damage, and anti -fibrotic actions with reduced glomerulosclerosis and interstitial fibrosis 33,34 .…”

“…Several renal beneficial effects have been described in animal models of diabetic and non -diabetic nephropathy, human cell lines and even in human studies for all DPP -4 inhibitors available 34 . These include anti -oxidative and anti -inflammatory actions, decreased podocyte loss, decreased albuminuria, decreased tubular damage, and anti -fibrotic actions with reduced glomerulosclerosis and interstitial fibrosis 33,34 . A detailed description of all molecular mechanisms potentially involved in these effects is beyond the scope of this review.…”