Genistein Ameliorates Renal Fibrosis Through Regulation Snail via m6A RNA Demethylase ALKBH5.
Genistein Ameliorates Renal Fibrosis Through Regulation Snail via m6A RNA Demethylase ALKBH5.
复制标题
金雀异黄素通过 m6A RNA 去甲基化酶 ALKBH5 调节 Snail 改善肾纤维化
DOI：
10.3389/fphar.2020.579265
复制
发表时间：
2020
影响因子：
5.6
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Ning Y;Chen J;Shi Y;Song N;Yu X;Fang Y;Ding X
肾小管间质纤维化与慢性肾脏疾病进展有关，是肾脏老化的典型特征。纤维化易感基因的表观遗传修饰调节肾纤维化的发展。大豆异黄酮作为一种“表观遗传饮食”，具有肾脏保护作用和表观遗传调节作用。然而，其肾脏保护作用和潜在机制尚未完全阐明。在此，我们发现染料木黄酮在体内UUO（单侧输尿管闭塞）模型和体外模型中对肾脏上皮细胞表现出明显的抗纤维化作用。该机制与上皮-间质转化和m6 A RNA去甲基化酶ALKBH 5密切相关。由UUO诱导的小鼠纤维化肾脏表现出肾纤维化相关蛋白的不利表达和总m6 A水平的显著增加。ALKBH 5作为橡皮擦在肾纤维化过程中表现出更强的抑制作用。然而，染料木黄酮预处理显著恢复了ALKBH 5的丢失，并减少了肾纤维化、异常蛋白和炎症标志物。可能的机制研究表明，染料木素促进ALKBH 5的表达，并可能诱导一些上皮-间质转化相关转录因子mRNA m6 A甲基化水平的升高。我们发现，蜗牛是关键的调节和关键的染料木素的保护作用。为了验证ALKBH 5和snail之间的关系，我们在体外产生ALKBH 5的敲低和过表达细胞。ALKBH 5敲低增强间充质表型标记物α-平滑肌肌动蛋白和snail表达。一致的是，ALKBH 5的过度表达增加了上皮粘附分子E-钙粘蛋白，减少了snail的表达。总之，染料木黄酮在UUO诱导的肾纤维化中增加肾ALKBH 5表达，降低RNA m6 A水平，改善肾损伤。
Renal tubule-interstitial fibrosis is related to chronic kidney disease progression and a typical feature of the aging kidney. Epigenetic modifications of fibrosis-prone genes regulate the development of renal fibrosis. As a kind of “epigenetic diet”, soy isoflavone genistein was reported to have renal protective action and epigenetic-modulating effects. However, its renal protection role and underlying mechanisms are yet to be fully clarified. Herein, we showed that genistein exhibits a demonstrable anti-fibrotic effect on kidney in vivo UUO (unilateral ureteral occlusion) model and renal epithelial cells in vitro model. The mechanism is strongly associated with epithelial-to-mesenchymal transition and m6A RNA demethylase ALKBH5. Mouse fibrotic kidneys induced by UUO exhibited adverse expression of renal fibrosis-related proteins and significant increases in the total m6A level. As an eraser, ALKBH5 showed severer suppression in the renal fibrosis process. However, genistein pretreatment restored ALKBH5 loss remarkably and reduced renal fibrosis, abnormal protein, and inflammatory markers. The examination of possible mechanisms revealed that genistein promoted ALKBH5 and maybe induced the level of mRNA m6A methylation in some epithelial-to-mesenchymal transition-related transcription factors. We found snail was the critical regulator and critical for the protective role of genistein. To verify the relationship between ALKBH5 and snail, we generated knockdown and overexpression of ALKBH5 cells in vitro. ALKBH5 knockdown enhanced the mesenchymal phenotype marker α-smooth muscle actin and snail expression. In agreement, overexpression ALKBH5 increased epithelial adhesion molecule E-cadherin and reduced snail expression. In conclusion, genistein increased renal ALKBH5 expression in UUO-induced renal fibrosis and reduced RNA m6A levels and ameliorates renal damages.
登录
查看更多内容
Necrostatin-1 通过抑制细胞凋亡和氧化应激减轻顺铂诱导的肾毒性并保留 Klotho 表达
影响因子：
5.6
作者：
Ning Y;Shi Y;Chen J;Song N;Cai J;Fang Y;Yu X;Ji J;Ding X
通讯作者：
Ding X
影响因子：
2.3
作者：
Canyilmaz, Emine;Uslu, Gonca Hanedan;Yoney, Adnan
通讯作者：
Yoney, Adnan
影响因子：
7.8
作者：
Min KW;Zealy RW;Davila S;Fomin M;Cummings JC;Makowsky D;Mcdowell CH;Thigpen H;Hafner M;Kwon SH;Georgescu C;Wren JD;Yoon JH
通讯作者：
Yoon JH
影响因子：
5.9
作者：
Li WF;Yang K;Zhu P;Zhao HQ;Song YH;Liu KC;Huang WF
通讯作者：
Huang WF
METTL3/m(6)A/miRNA-873-5p 通过调节 Keap1/Nrf2 通路减轻粘菌素诱导的肾损伤中的氧化应激和细胞凋亡
影响因子：
5.6
作者：
Wang, Jian;Ishfaq, Muhammad;Li, Jichang
通讯作者：
Li, Jichang