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.
Sci Rep. 2016 Oct 5;6:34597. doi: 10.1038/srep34597.
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.
肾纤维化是慢性肾脏病（CKD）的标志，其发生和发展受到表观遗传修饰的显著影响。大黄酸是一种植物来源的蒽醌，具有很强的抗纤维化作用，但它的保护作用机制仍不完全清楚。在这里，我们通过研究大黄酸对 Klotho 的调节作用来探讨大黄酸抗肾纤维化的机制，Klotho 是一种已知的肾抗纤维化蛋白，其在肾损伤后的抑制作用据报道涉及异常的 DNA 甲基化。我们报告说，大黄酸是 Klotho 的一个令人印象深刻的上调因子，它显著逆转了单侧输尿管梗阻诱导的纤维化肾脏中 Klotho 的下调。进一步的检查表明，纤维化肾脏中 Klotho 的丢失与 Klotho 启动子的高甲基化有关，这是由于异常的甲基转移酶 1 和 3a 的表达。然而，大黄酸显著纠正了所有这些表观遗传改变，随后减轻了促纤维化蛋白的表达和肾纤维化，而通过 RNA 干扰敲低 Klotho 则很大程度上阻断了大黄酸的抗肾纤维化作用，这表明大黄酸对 Klotho 丢失的表观遗传逆转是赋予大黄酸抗肾纤维化功能的关键作用模式。总之，我们的研究揭示了大黄酸在防止 Klotho 丢失和肾纤维化方面的新型去甲基化特性，并证明了 Klotho 靶向的表观遗传干预在治疗与肾纤维化相关的肾脏疾病方面的有效性。
