title: Rhein reversal of DNA hypermethylation-associated Klotho suppression ameliorates renal fibrosis in mice.
abstract: 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 Klotho-targeted epigenetic intervention in potential treatment of renal fibrosis-associated kidney diseases.
authors.affiliation: Division of Nephrology, Jinling Hospital, Southern Medical University, Nanjing, 210016, China.|National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Key lab of Jiangsu molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Yin
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Jinling Hospital, Southern Medical University, Nanjing, 210016, China.|National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210016, China.|The Key lab of Jiangsu molecular Medicine, Nanjing University School of Medicine, Nanjing, 210093, China.
authors.forename: Wangsen
authors.initials: W
authors.lastname: Cao
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005355:Fibrosis; D005966:Glucuronidase / Q000096:biosynthesis* / Q000235:genetics; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000880:Anthraquinones; D005966:Glucuronidase; D000090265:Klotho Proteins; C020491:rhein