赖氨酸甲基转移酶SMYD2在顺铂致肾脏纤维化中的作用及机制研究

顺铂是临床常用抗肿瘤药，长期使用会引起肾纤维化，目前无有效防治措施。研究证实，组蛋白赖氨酸甲基转移酶SMYD2在多种肿瘤中高表达且参与调控上皮-间充质转分化（EMT），但SMYD2在肾纤维化中的表达和作用尚未见研究报道。我们发现，顺铂致肾纤维化小鼠肾组织及体外诱导EMT的肾小管上皮细胞（RTECs）中SMYD2和TGF-β1均高表达，抑制SMYD2可阻断EMT发生。据此我们推测SMYD2可能通过激活TGF-β1信号通路调控肾纤维化发生发展。故本研究拟利用顺铂致肾纤维化小鼠模型和体外培养RTECs，通过SMYD2抑制剂、基因敲除和siRNA基因沉默等，首先评估抑制SMYD2对顺铂致肾纤维化小鼠肾功能和纤维化的影响；其次明确SMYD2对部分EMT的调控作用及分子机制；最后阐明SMYD2在激活TGF-β1通路中的作用及机制。本研究将为顺铂致肾纤维化的有效防治探寻研究新靶点和研发新药奠定基础。

Cisplatin is a widely used anti-tumor drug, however, administration of multiple cycles of cisplatin leads to renal fibrosis. Currently, there is no available approach to prevent and treat cisplatin-induced renal fibrosis . Histone lysine methyltransferase SMYD2 is highly expressed in multiple cancers and the abnormal expression of SMYD2 regulates the epithelial-to-mesenchymal transition (EMT) process in tumor cells , but the expression and role of SMYD2 in renal fibrosis have not been reported. Recently, We have previously found that SMYD2 and transforming growth factor-β1(TGF-β1) are highly expressed in the kidney of cisplatin-induced renal fibrosis and in cultured renal tubular epithelial cells with EMT. Furthermore, pharmaceutical inhibition of SMYD2 could significantly attenuate the partial EMT induced by TGF-β1 in vitro. Based on this, we hypothesized that SMYD2 activation may regulate development and progression of cisplatin-induced renal fibrosis via TGF-β1signaling pathway. In this study, by SMYD2 inhibition via SMYD2 inhibitors, SMYD2 knockout and SMYD2 siRNA in a murine model of cisplatin-induced renal fibrosis and partial EMT renal tubular epithelial cells induced by cisplatin, and a variety of molecular techniques, we will (1) evaluate the effect of SMYD2 inhibition on the renal dysfunction and pathogenesis of renal fibrosis, (2) explore the role and molecular mechanisms of SMYD2 in regulating cisplatin-elicited partial EMT of renal tubular epithelial cells, and (3) elucidate the role and molecular mechanisms of SMYD2 in regulating the activation of TGF-β1signaling pathway. Therefore, the project will lay the foundation for identification of novel targets for treatment of cisplatin-induced renal fibrosis and development of drugs for preventing and treating cisplatin-elicited renal fibrosis.