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.
Highlights
Serum blood urea nitrogen (BUN) and creatinine levels significantly increased in adenine-fed rats compared to the control group, which confirmed the establishment of a chronic kidney disease (CKD) model
Adenine-fed rats showed a remarkable increase in calcium deposition in the media layer of the abdominal aorta compared to that observed for the control group, whereas calcium deposition was significantly reduced by a high dose (20 mg/kg) of gemigliptin (Fig 1A and 1B)
We investigated the change of RUNX2 expression using immunohistochemistry (Fig 1C) and western blot analysis (Fig 1D)
Summary
Vascular calcification (VC) occurs more frequently in patients with chronic kidney disease (CKD) and diabetes mellitus (DM), and usually affects blood vessels including the aorta as well. Recently VC has been recognized as a highly active process It is associated with a multifactorial mechanism, which includes calcium/phosphate dysregulation, calciprotein particles, impaired anti-calcific mechanism such as dysfunction of inhibitors, and trans-differentiation of vascular smooth muscle cell (VSMC) phenotype. VSMCs trans-differentiation is characterized by loss of VSMC marker proteins [smooth muscle (SM) α-actin and SM22α] and gain of osteoblast marker proteins [runt-related transcription factor-2 (RUNX2; called CBFA1), osterix (OSX), osteocalcin (OC), DMP-1, sclerostin (SOST), and E11] This is a process similar to physiological bone formation [6]. Previous studies have reported on the pleiotropic effect of gemigliptin, besides its glucose lowering effect, including inhibition of LPS-induced pro-inflammatory effects in vascular endothelial cells by attenuating NF-kappaB and JNK signaling via Akt/ AMPK-dependent mechanisms [21], and protection against renal interstitial fibrosis in a mouse model of ureteral obstruction [22]. DPP-4 inhibitor gemigliptin protects against vascular calcification attenuates VC in an adenine-induced CKD model and to explore the possible mechanisms by which gemigliptin is involved in this process using cultured VSMCs
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