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

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 calcificat...

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Published in:PloS one 2017-07, Vol.12 (7), p.e0180393-e0180393
Main Authors: Choi, Soon-Youn, Ryu, Hye-Myung, Oh, Eun-Joo, Choi, Ji-Young, Cho, Jang-Hee, Kim, Chan-Duck, Kim, Yong-Lim, Park, Sun-Hee
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Adenine
AKT protein
Analysis
Animals
Antidiabetics
Aorta
Aorta, Abdominal - drug effects
Aorta, Abdominal - metabolism
Aorta, Abdominal - pathology
Attenuation
Biocompatibility
Biology and Life Sciences
Biomedical materials
Calcification
Calcification (ectopic)
Calcification (Physiology)
Calcium
Calcium - metabolism
Calcium content
Calcium phosphates
Cbfa-1 protein
Chronic kidney failure
Complications and side effects
Core Binding Factor Alpha 1 Subunit - genetics
Core Binding Factor Alpha 1 Subunit - metabolism
Diabetes
Diabetes mellitus
Differentiation
Dipeptidyl-peptidase IV
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Dkk1 protein
Dosage and administration
Drug therapy
Drugs
Frizzled protein
Frizzled Receptors - genetics
Frizzled Receptors - metabolism
Gene expression
Gene Expression Regulation
Genetic aspects
Hypoglycemic agents
Inhibitors
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Internal medicine
Kidney diseases
Kinases
Male
Markers
Medicine
Medicine and Health Sciences
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Myocytes, Smooth Muscle - pathology
NAD(P)H oxidase
NADPH Oxidase 4
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Nephrology
NOX4 protein
Oxidase
Oxidative stress
Oxygen
Peptidase
Phosphate
Phosphates
Phosphates - antagonists & inhibitors
Phosphates - pharmacology
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Physical Sciences
Piperidones - pharmacology
Pit1 protein
Primary Cell Culture
Proteins
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Pyrimidines - pharmacology
Rats
Rats, Sprague-Dawley
Reactive oxygen species
Reactive Oxygen Species - antagonists & inhibitors
Reactive Oxygen Species - metabolism
Renal Insufficiency, Chronic - chemically induced
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - metabolism
Renal Insufficiency, Chronic - pathology
Research and Analysis Methods
Rodents
Signal transduction
Smooth muscle
SOST protein
Studies
Transcription Factor Pit-1 - antagonists & inhibitors
Transcription Factor Pit-1 - genetics
Transcription Factor Pit-1 - metabolism
Transcription factors
Vascular Calcification - genetics
Vascular Calcification - metabolism
Vascular Calcification - pathology
Vascular Calcification - prevention & control
Wnt protein
Wnt Signaling Pathway
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0180393