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Sci Rep:南京大学曹望森课题组发表慢性肾脏病表观遗传机制和干预研究论文

摘要 : 2017年10月19日,国际学术权威刊物自然出版集团旗下子刊《Scientific Reports》杂志在线发表了南京大学医学院曹望森教授课题组与刘志红院士等人合作的一篇研究论文,研究报道了慢性肾脏病表观遗传机制和干预研究进展。

2017年10月19日,国际学术权威刊物自然出版集团旗下子刊《Scientific Reports》杂志在线发表了南京大学医学院曹望森教授课题组与刘志红院士等人合作的一篇研究论文,研究报道了慢性肾脏病表观遗传机制和干预研究进展。

慢性肾脏病发病率高,认知率低,常并发心血管和骨质损害,是严重危害人类健康的重大疾病,其发病机理不明并缺乏有效治疗手段。最新研究表明表观遗传因素在慢性肾脏病的发生发展中扮演重要角色。曹望森课题组从肾脏抗衰老蛋白Klotho入手,以慢性肾脏病和肾脏纤维化小鼠为模型,研究DNA甲基化异常导致慢性肾脏病Klotho缺失的表观遗传机制和有效干预手段,证明慢性肾脏病Klotho缺失主要由DNA甲基化酶DNMT1/3a异常相关的Klotho启动子超甲基化介导,而中药成分大黄酸能够通过逆转DNMT1/3a异常和Klotho启动子超甲基化维持肾脏Klotho水平,有效缓解慢性肾脏病及相关的肾脏纤维化和骨质疏松病变。

接着,该课题组进一步探索了慢性肾脏病DNA甲基化异常导致Klotho缺失的上游病理因素,发现TGFb是导致慢性肾脏病DNA甲基化异常的主因。TGFb通过抑制miR-30和MiR-148分别高调DNMT1和DNMT3a导致Klotho启动子超甲基化下调促进了肾脏纤维化的发生发展。

蛋白质乙酰化是另一个重要表观遗传修饰现象,以往研究表明抑制组蛋白去乙酰化酶能够有效缓解慢性肾病理损伤和骨质异常,但机理不明。该课题组发现组蛋白去乙酰化酶抑制剂通过抑制HDAC3促进PPARg赖氨酸240和265乙酰化进而增加了PPARg对Klotho的转录活性,通过逆转Klotho下调缓解慢性肾病和相关的骨质损伤。系列研究论文为阐明慢性肾脏病表观遗传机制和设计有效干预措施提供了新的思路。

原文链接:

Rhein reversal of DNA hypermethylation-associated Klotho suppression ameliorates renal fibrosis in mice

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.

来源: Scientific Reports 浏览次数:0

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