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

Date Published: July 7, 2017

Publisher: Public Library of Science

Author(s): Soon-Youn Choi, Hye-Myung Ryu, Eun-Joo Oh, Ji-Young Choi, Jang-Hee Cho, Chan-Duck Kim, Yong-Lim Kim, Sun-Hee Park, Xing-Ming Shi.


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.

Partial Text

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 as medium- and small-sized vessels such as coronary arteries [1]. It is characterized by accelerated mineral deposition within the medial layer of arteries. VC increases the stiffness of the arterial wall and negatively influences heart function by increasing cardiac afterload and left ventricular hypertrophy, and decreasing coronary blood flow. Clearly, VC has an impact on cardiovascular events and mortality in CKD patients as well as patients with DM [2–4]. Hyperphosphatemia, one of the major abnormalities in CKD-mineral bone disorder (MBD), is primarily associated with VC in patients with kidney disease. Previously, high phosphate-induced VC was reported to indicate passive calcium-phosphate deposition [5]. However, 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; also called CBFA1), osterix (OSX), osteocalcin (OC), DMP-1, sclerostin (SOST), and E11]. This is a process similar to physiological bone formation [6]. In addition, Wnt signaling has been reported as a main master regulator for activating the expression of osteoblast trans-differentiation markers to induce VC [7]. Wnt proteins bind to the plasma membrane frizzled (FDZ) receptors and low-density lipoprotein receptor-related protein-5/6 (LRP5/6) co-receptor, and regulate downstream signaling by dephosphorylation of β-catenin. Activation of Wnt signaling regulates trans-differentiation of the osteogenic phenotype through the expression of several bone-related proteins such as osterix (OSX), osteocalcin (OC), and sclerostin (SOST) [8].

In this study, for the first time, we investigated the protective effect of gemigliptin against VC in an adenine-induced CKD model and in cultured VSMCs. Using a rat model of adenine-induced CKD, we demonstrated an increased VC in abdominal aortic wall. Gemigliptin treatment significantly reduced VC and attenuated the expression of the osteogenic marker, RUNX2. The protective effect of gemigliptin on VC was independent of the level of serum phosphorus. Similarly, a previous report showed that the protective effect of diosgenin against VC depends on the direct action on VSMCs regardless of blood chemistry [28].




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