Dipeptidyl peptidase-4 inhibitor gemigliptin protects against vascular calcification in an experimental chronic kidney disease and vascular smooth muscle cells

Abstract

Although dipeptidyl peptidase-4 inhibitors, a class of antidiabetic drugs, have various pleiotropic effects, it remains undetermined whether gemigliptin has a beneficial effect on vascular calcification. Therefore, this study was performed to evaluate the effect of gemigliptin on vascular calcification in a rat model of adenine-induced chronic kidney disease and in cultured vascular smooth muscle cells. Gemigliptin attenuated calcification of abdominal aorta and expression of RUNX2 in adenine-induced chronic kidney disease rats. In cultured vascular smooth muscle cells, phosphate-induced increase in calcium content was reduced by gemigliptin. Gemigliptin reduced phosphate-induced PiT-1 mRNA expression, reactive oxygen species generation, and NADPH oxidase mRNA expression (p22phox and NOX4). The reduction of oxidative stress by gemigliptin was associated with the downregulation of phospho-PI3K/AKT expression. High phosphate increased the expression of frizzled-3 (FDZ3) and decreased the expression of dickkopf-related protein-1 (DKK-1) in the Wnt pathway. These changes were attenuated by gemigliptin treatment. Gemigliptin restored the decreased expression of vascular smooth muscle cells markers (α-SMA and SM22α) and increased expression of osteogenic makers (CBFA1, OSX, E11, and SOST) induced by phosphate. In conclusion, gemigliptin attenuated vascular calcification and osteogenic trans-differentiation in vascular smooth muscle cells via multiple steps including downregulation of PiT-1 expression and suppression of reactive oxygen species generation, phospho-PI3K/AKT, and the Wnt signaling pathway.

Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease

“…Ang II increases ROS and cytokine production; thus, similar to the NHE1 modulation, we suggest that the mechanisms underlying the antioxidant and anti-inflammatory effects of sitagliptin may be both dependent on counteracting the effects of Ang II and Ang II-independent. The Ang II-independent antioxidant and anti-inflammatory effects of DPPIV inhibition are supported by in vitro studies in which the DPPIV inhibitor gemigliptin reduced the ROS generation, reduced the expression of NADPH oxidase ( NOX4 , p22 phox subunit) mRNA induced by exposing vascular smooth muscle cells to high phosphate [38] and reduced the expression of MCP-1 [39].…”

Effect of Dipeptidyl Peptidase- 4 (DPP-4) Inhibitor on Biomarkers of Kidney Injury and Vascular Calcification in Diabetic Nephropathy: A Randomized Controlled Trial

“…To give 80% power at P<0.05 to detect a difference in biomarker levels of vascular calci cation after gemigliptin treatment in CKD patients, a total of 100 patients per group were required, and 182 subjects total were recruited. 4 From September 2018 to October 2020, we collected baseline data from all participants for demographic characteristics, comorbid conditions and physical examination. Blood samples were collected and allowed to clot for 30 min at room temperature before centrifugation for 15 minutes.…”

Natural and non-natural antioxidative compounds: potential candidates for treatment of vascular calcification

“…Multiple non-natural chemicals/medications also exhibit antioxidant properties and are effective against VC. We identified 19 types of such candidates with potential therapeutic effects against VC: acetylcysteine 33 , alendronate 49 , BMP inhibitor 39 , dimethyl fumarate 47 , farnesyltransferase inhibitor 41 , gemigliptin 57 , growth hormone-releasing hormone (GHRH) receptor agonist 58 , metformin 42 , pentoxifylline 64 , pravastatin 33 , pyrrolidine dithiocarbamate (PDTC) 34 , simvastatin 32 , sodium hydrosulfide 53 , sodium selenite 37,45 , STS 36,43,44 , Tempol 40 , TRAM-34 46 , topical poly(1,8-octamethylene-citrate-co-cysteine) (POCC) 54 , and hydrogen peroxide 51 . Among these, 11 (57.9%) were medications with specific clinical indications, while 8 (42.1%) were non-medicinal chemicals.…”

“…Gemigliptin belongs to the dipeptidyl peptidase-4 inhibitor class of antidiabetic agents, which exhibit a pleiotropic effect through glucagon-like peptide-1 (GLP-1)-dependent and -independent mechanisms including insulin sensitization and the inhibition of oxidation and apoptosis 82 . Choi et al reported that gemigliptin attenuated VC through a variety of beneficial molecular alterations, including decreased expressions of PiT-1 and Nox4 with reduced ROS production, and suppressed PI 3 K-Akt and Wnt-FDZ pathway activities 57 . On the other hand, metformin has been shown to ameliorate VSMC calcification through AMPK-independent (BMP-2 inhibition) and AMPK-dependent (AMPK and eNOS activation) mechanisms 42 .…”