期刊
SCIENTIFIC REPORTS
卷 6, 期 -, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/srep34597
关键词
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资金
- National Basic Research Program of China 973 Program [2012CB517606]
- National Nature Science Foundation of China [81271301, 81470940, 81670672]
- Major International (Regional) Joint Research Project [81320108007]
Renal fibrosis is the hallmark of chronic kidney diseases (CKD) and its development and progression are significantly affected by epigenetic modifications. Rhein, a plant-derived anthraquinone, displays strong anti-fibrosis properties, but its protective mode of action remains incompletely understood. Here we explore the mechanism of Rhein anti-renal fibrosis by investigating its regulation of Klotho, a known renal anti-fibrotic protein whose suppression after renal injury reportedly involves aberrant DNA methylation. We report that Rhein is an impressive up-regulator of Klotho and it markedly reversed Klotho down-regulation in unilateral ureteral occlusion-induced fibrotic kidney. Further examinations revealed that Klotho loss in fibrotic kidney is associated with Klotho promoter hypermethylation due to aberrant methyltransferase 1 and 3a expressions. However, Rhein significantly corrected all these epigenetic alterations and subsequently alleviated pro-fibrotic protein expression and renal fibrosis, whereas Klotho knockdown via RNA interferences largely abrogated the anti-renal fibrotic effects of Rhein, suggesting that Rhein epigenetic reversal of Klotho loss represents a critical mode of action that confers Rhein's anti-renal fibrotic functions. Altogether our studies uncover a novel hypomethylating character of Rhein in preventing Klotho loss and renal fibrosis, and demonstrate the efficacy of Klothotargeted epigenetic intervention in potential treatment of renal fibrosis-associated kidney diseases.
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