title: Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease.
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 asin vitroandin vivomodels, 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.
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.; Kidney and Dialysis Institute of Shanghai, Shanghai, China.; Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.; Kidney and Dialysis Institute of Shanghai, Shanghai, China.; Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Tongqiang
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Kidney and Dialysis Institute of Shanghai, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Teng
authors.affiliation: Kidney and Dialysis Institute of Shanghai, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.; Kidney and Dialysis Institute of Shanghai, Shanghai, China.; Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Ding
mesh_terms: D000818:Animals; D002460:Cell Line; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics*; D006801:Humans; D007200:Indican / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D000090265:Klotho Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D061205:Vascular Calcification / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D005966:Glucuronidase; D000090265:Klotho Proteins; D007200:Indican
keywords: Chronic kidney disease.; DNA methylation; DNA methyltransferase; Indoxyl sulfate; Klotho; Vascular calcification