组蛋白甲基化转移酶SMYD2在糖尿病肾病中的作用及机制研究

糖尿病肾病(DN)已成为导致慢性肾衰竭的主要原因，其发病机制仍未完全阐明，目前尚无有效治疗措施。我们前期研究发现：组蛋白甲基化转移酶SMYD2在体外血清/转化生长因子诱导活化的肾成纤维细胞、发生上皮-间充质转分化（EMT）的肾小管上皮细胞（TECs）及DN小鼠肾组织中高表达，SMYD2抑制剂可抑制肾成纤维细胞活化及TECs发生EMT。提示SMYD2可能调控DN肾纤维化发生发展，但其具体机制尚不清楚，迄今亦未见相关文献报道。本研究拟利用DN小鼠模型、高糖培养的肾成纤维细胞和TECs，通过基因敲除、药物抑制和siRNA基因沉默等，首先评估抑制SMYD2对DN小鼠肾功能及肾脏病理改变的影响；其次探讨SMYD2对肾成纤维细胞增殖活化及肾小管EMT的作用和机制；最后阐明SMYD2在DN中的作用和机制。本研究有望首次明确SMYD2对DN肾纤维化的作用及分子机制，为DN防治探寻新靶点和研发新药奠定基础。

Diabetic nephropathy (DN) is a major cause of chronic renal failure due to renal fibrosis. Currently，there is no available approach to prevent and treat DN because the pathogenesis of DN is unclear. Recently, we have found that SMYD2，a critical histone methyltransferase, is highly expressed in activated renal fibroblasts and cultured renal tubular epithelial cells with epithelial-to-mesenchymal transition (EMT), and in the kidney of DN mice with kidney fibrosis. Furthermore, pharmaceutical inhibition of SMYD2 could significantly attenuate the activation of the renal fibroblasts and the EMT of renal tubular epithelial cells induced by serum or transforming growth factor-β1 in vitro. This suggests that SMYD2 methylation may play a critical role in development and progression of DN, but its specific mechanism is not yet clear. By SMYD2 inhibition via SMYD2 inhibitor, SMYD2 knockout and SMYD2 siRNA in a murine model of DN, activated renal fibroblasts and EMT renal tubular epithelial cells induced by high glucose. we will (1) evaluate the effect of SMYD2 inhibition on the renal dysfunction and pathogenesis of DN; (2) explore the role and molecular mechanisms of SMYD2-elicited activation and proliferation of fibroblasts and EMT of renal tubular epithelial cells; (3) elucidate the role and mechanisms of SMYD2 in regulating DN-elicited renal fibrosis. Therefore, the successful completion of this project will lay down the ground work for identification of novel targets for treatment of DN-elicited renal fibrosis and development of epigenetic drugs for preventing and treating DN.