期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 6, 期 11, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.117.007248
关键词
calcification; chronic kidney disease; nuclear factor-kappa B; smooth muscle cell
资金
- Japan Society for the Promotion of Science [16K09655, 15K09271]
- Japanese Association of Dialysis Physicians (JADP) [2013-5, 2016-9]
- Kidney Foundation, Japan [JFKB14-33]
- Grants-in-Aid for Scientific Research [16K09655, 15K09271] Funding Source: KAKEN
Background-Hyperphosphatemia is a major factor promoting the formation of arterial medial calcification in chronic kidney disease (CKD). However, arterial medial calcification begins to occur during the early stages of CKD, when hyperphosphatemia is not yet apparent. It is predicted that other factors also play a role. The aim of the present study was to determine the role of proinflammatory nuclear factor-kappa B (NF-kappa B) signaling in smooth muscle cells (SMCs) for phosphate-induced arterial medial calcification in CKD mice. Methods and Results-We first sought to establish a novel mouse model of CKD with arterial medial calcification. CKD was induced in DBA/2 mice by feeding them a low concentration of adenine, and these mice were fed a normal or high-phosphorus diet. Severe calcification was seen in CKD mice fed the high-phosphorus diet, while it was undetectable in CKD mice fed the normal phosphorus diet or control mice fed the high-phosphorus diet. Arterial medial calcification was accompanied by phenotypic switching of SMCs into osteogenic cells. Interestingly, NF-kappa B inhibitors, tempol and triptolide, both reduced arterial medial calcification in CKD mice fed the high-phosphorus diet. Moreover, formation of arterial medial calcification, as well as SMC phenotypic switching, was also markedly attenuated in transgenic mice, in which the NF-kappa B activity was inhibited selectively in SMCs. Mechanistic studies revealed that Kruppel-like factor 4 was involved in NF-kappa B-induced SMC phenotypic switching and calcification. Conclusions-Results of the present studies suggest that the NF-kappa B signaling in SMCs plays an important role in high phosphate-induced arterial medial calcification in CKD.
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