2017年10月19日, 國際學術權威刊物自然出版集團旗下子刊《Scientific Reports》雜誌線上發表了南京大學醫學院曹望森教授課題組與劉志紅院士等人合作的一篇研究論文, 研究報導了慢性腎臟病表觀遺傳機制和干預研究進展。
慢性腎臟病發病率高, 認知率低, 常併發心血管和骨質損害, 是嚴重危害人類健康的重大疾病, 其發病機理不明並缺乏有效治療手段。 最新研究表明表觀遺傳因素在慢性腎臟病的發生發展中扮演重要角色。 曹望森課題組從腎臟抗衰老蛋白Klotho入手, 以慢性腎臟病和腎臟纖維化小鼠為模型,
接著, 該課題組進一步探索了慢性腎臟病DNA甲基化異常導致Klotho缺失的上游病理因素, 發現TGFb是導致慢性腎臟病DNA甲基化異常的主因。 TGFb通過抑制miR-30和MiR-148分別高調DNMT1和DNMT3a導致Klotho啟動子超甲基化下調促進了腎臟纖維化的發生發展。
蛋白質乙醯化是另一個重要表觀遺傳修飾現象, 以往研究表明抑制組蛋白去乙醯化酶能夠有效緩解慢性腎病理損傷和骨質異常,
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原文摘要:
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, wheras 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.