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Int J Biol Sci 2016; 12(10):1236-1246. doi:10.7150/ijbs.15195

Research Paper

Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease

Jing Chen1,2,3*, Xiaoyan Zhang1,2,3✉*, Han Zhang1, Tongqiang Liu1, Hui Zhang1, Jie Teng2, Jun Ji2, Xiaoqiang Ding1,2,3✉

1. Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
2. Kidney and Dialysis Institute of Shanghai, Shanghai, China.
3. Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
*These authors contributed equally.

Abstract

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.

Keywords: DNA methylation, DNA methyltransferase, Klotho, Indoxyl sulfate, Vascular calcification, Chronic kidney disease.

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How to cite this article:
Chen J, Zhang X, Zhang H, Liu T, Zhang H, Teng J, Ji J, Ding X. Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease. Int J Biol Sci 2016; 12(10):1236-1246. doi:10.7150/ijbs.15195. Available from http://www.ijbs.com/v12p1236.htm