Targeting lysine-specific demethylase 1A inhibits renal epithelial-mesenchymal transition and attenuates renal fibrosis.
Targeting lysine-specific demethylase 1A inhibits renal epithelial-mesenchymal transition and attenuates renal fibrosis.
复制标题
靶向赖氨酸特异性脱甲基酶1a抑制肾上皮 - 间质转变并减弱肾纤维化。
DOI：
10.1096/fj.202101566r
复制
发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
赖氨酸特异性组蛋白去甲基化酶 1 (LSD1) 作为第一个被识别的组蛋白/赖氨酸去甲基化酶，可调节多种疾病中的基因表达和蛋白质功能。在这项研究中，我们发现，在患有单侧输尿管梗阻（UUO）的小鼠肾脏和经历TGF-β1诱导的上皮间质转化（EMT）的培养的NRK-52E细胞中，LSD1的表达增加。用其特异性抑制剂 ORY1001 抑制 LSD1 可减轻肾脏 EMT 和纤维化，这与细胞外基质蛋白沉积和纤维化标志物（包括 α-平滑肌肌动蛋白 (α-SMA) 和纤连蛋白）表达减少有关，以及 UUO 肾脏和 TGF-β1 诱导的 NRK-52E 细胞中 E-钙粘蛋白表达的恢复和 N-钙粘蛋白表达的减少有关。在 UUO 肾脏和用 TGF-β1 处理的 NRK-52E 细胞中，靶向 LSD1 还降低了 Snail 家族转录阻遏蛋白 1 (Snail-1) 的表达及其与 LSD1 的相互作用。此外，我们还发现了一个新的LSD1-14-3-3z-PKCα轴来调节AKT和Stat3的激活，进而调节成纤维细胞的激活。这项研究表明LSD1通过激活多种信号通路在肾EMT和纤维化的调节中发挥着关键作用，并强调LSD1有潜力作为治疗肾纤维化的治疗靶点。
Lysine-specific histone demethylase 1 (LSD1) as the first identified histone/lysine demethylase regulates gene expression and protein functions in diverse diseases. In this study, we show that the expression of LSD1 is increased in mouse kidneys with unilateral ureteral obstruction (UUO) and in cultured NRK-52E cells undergoing TGF-β1-induced epithelial–mesenchymal transition (EMT). Inhibition of LSD1 with its specific inhibitor ORY1001 attenuated renal EMT and fibrosis, which was associated with decreased the deposition of extracellular matrix proteins and the expression of fibrotic markers, including α-smooth muscle actin (α-SMA) and fibronectin, and the recovery of E-cadherin expression and decrease of N-cadherin expression in UUO kidneys and in NRK-52E cells induced with TGF-β1. Targeting LSD1 also decreased the expression of Snail family transcriptional repressor 1 (Snail-1) and its interaction with LSD1 in UUO kidneys and in NRK-52E cells treated with TGF-β1. In addition, we identified a novel LSD1-14-3-3ζ-PKCα axis in the regulation of the activation of AKT and Stat3 and then the activation of fibroblasts. This study suggests that LSD1 plays a critical role in regulation of renal EMT and fibrosis through activation of diverse signaling path- ways and places an emphasis that LSD1 has potential as a therapeutic target for the treatment of renal fibrosis.
影响因子：
2.9
作者：
Kittirat Y;Techasen A;Thongchot S;Loilome W;Thanan R;Yongvanit P;Sungkhamanon S;Titapun A;Khuntikeo N;Namwat N
通讯作者：
Namwat N