Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 12, Issue 10, Pages 1236-1246Publisher
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.15195
Keywords
DNA methylation; DNA methyltransferase; Klotho; Indoxyl sulfate; Vascular calcification; Chronic kidney disease
Categories
Funding
- Ministry of Science and Technology of People's Republic of China [2011BAI10B03]
- Science and Technology Commission of Shanghai Municipality [14ZR1406400]
- Young Physician Training Program from Shanghai Health and Family Planning Commission
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Chronic kidney disease (CKD) is a state of Klotho deficiency. The Klotho expression may be suppressed due to DNA hypermethylation in cancer cells so we have investigated the effects and possible mechanisms by which Klotho expression is regulated in human aortic smooth muscle cells (HASMCs). The vascular Klotho hypermethylation in radial arteries of patients with end-stage renal disease was described. Cultured HASMCs and 5/6-nephrectomized Sprague Dawley (SD) rats treated with indoxyl sulfate (IS) were used as in vitro and in vivo models, respectively. IS increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in HASMCs, and potentiated HASMCs calcification. The expression of DNA methyltransferase (DNMT) 1 and 3a in HASMCs treated with IS was significantly increased and specific inhibition of DNA methyltransferase 1 by 5-aza-2'-deoxycytidine(5Aza-2dc) caused demethylation of the Klotho gene and increased Klotho expression. In rats, injection of IS potentiated vascular calcification, increased CpG hypermethylation of the Klotho gene and decreased Klotho expression in the aortic medial layer and all of these changes could be reverted by 5Aza-2dc treatment. Transcriptional suppression of vascular Klotho gene expression by IS and epigenetic modification of Klotho by IS may be an important pathological mechanism of vascular calcification in CKD.
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