Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5888104 | Experimental and Molecular Pathology | 2014 | 7 Pages |
Abstract
Arterial medial calcification is a major complication in patients with chronic kidney disease and diabetes. It has been hypothesized that a high concentration of inorganic phosphate (Pi) induces calcification in vascular smooth muscle cells (vSMCs). However, the role of transforming growth factor-β (TGF-β)/Smad3 signaling in Pi-induced vascular calcification remains controversial. The aim of this study was to investigate the possible involvement of Smad3 in Pi-induced vascular calcification. We compared the degree of Pi-induced vSMC calcification between vSMCs isolated from wild-type (Smad3+/+) and Smad3-deficient (Smad3â/â) mice. We found that vSMCs from Smad3+/+ mice had less calcium (Ca) than those from Smad3â/â mice when they were exposed to high concentrations of Pi and Ca (Pi + Ca). The phosphorylation of Smad3 was induced in Smad3+/+ vSMCs by exposure to Pi + Ca. The concentration of extracellular pyrophosphate (ePPi) was lower in Smad3â/â vSMCs than in Smad3+/+ vSMCs and was significantly increased in Smad3+/+ vSMCs by treatment with TGF-β1. Also, the addition of a small amount of PPi to culture medium significantly decreased the deposition of Ca in both Smad3+/+ and Smad3â/â vSMCs. Ectonucleotide phosphatase/phosphodiesterase1 (Enpp1) was decreased at the mRNA, protein, and enzymatic activity levels in Smad3â/â vSMCs compared with Smad3+/+ vSMCs. A ChIP assay showed that phosphorylated Smad3 directly binds to the Enpp1 gene. Furthermore, the calcification of aortic segments was attenuated by treatment with TGF-β1 only in Smad3+/+ mice. Taken together, we conclude that Pi-induced vSMC calcification is suppressed by Smad3 via an increase in ePPi.
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Authors
Aiko Shimokado, Yujing Sun, Masako Nakanishi, Fuyuki Sato, Kosuke Oikawa, Takashi Akasaka, Yasuteru Muragaki,