糖尿病肾病(DN)已成为导致慢性肾衰竭的主要病因，其发病机制仍未充分明确，且尚无有效治疗措施。SnoN是TGF-β1/Smads通路的负调节因子，我们的研究表明肾小管上皮细胞SnoN蛋白表达减少可能是DN肾纤维化进行性发展的重要因素，但其调控机制仍有待阐明。BMP-7具有对抗TGF-β1致纤维化的效应，然而具体作用机制迄今不甚清楚。其他作者和我们近期的研究提示，恢复内源性SnoN蛋白表达水平可能是BMP-7抗TGF-β1致肾纤维化效应的重要机制。但在DN时，BMP-7调控SnoN表达的具体作用环节和机制尚不清楚。本项目以DM大鼠肾组织和高糖培养的RTECs为对象，采用分子生物学方法，明确BMP-7抗肾纤维化效应是否通过调控SnoN的表达实现，并评价BMP-7对SnoN表达的影响，为深入阐明DN的发病机制及有效治疗措施奠定实验基础。

Diabetic nephropathy (DN) has become a major cause of chronic renal failure, but the pathogenesis of DN is dimly known and without effective treatment. SnoN, as a negative regulator of TGF-β1/Smads pathway, which protein expression reduced with the development of renal fibrosis accelerates pathogenesis based on our studies. However, the mechanisms related to the regulation of SnoN remain to be elucidated yet. Bone morphogenetic protein-7(BMP-7) contributes to resist the effects of fibrosis TGF-β1 induced, but the mechanism is in a dilemma. Other researchs and our recent studies indicated that restoring the protein level of endogenous SnoN may be an important mechanism referred to the effects of BMP-7 against renal fibrosis TGF-β1 mediated. But at present, it remain unknown that BMP-7 mediated patterns and molecular mechanism of action emphasis on regulation of SnoN expression in DN. Kidney tissues of rats with diabetes mellitus(DM) and renal tubular epithelial cells under high-glucose cultivation as the research object,we intend to apply molecular biology approach to explicit whether the effects of BMP-7 objects to renal fibrosis on account of regulating the expression of SnoN.Meanwhile, this study will also focus on the regulation of SnoN expression BMP-7 mediated。For purpose of providing the the basic for further elucidate the pathogenesis of DN and the effective treatment of DN.

糖尿病肾病(DN)已成为导致慢性肾衰竭的主要病因，其发病机制仍未充分明确，且尚无有效治疗措施。SnoN是TGF-β1/Smads通路的负调节因子，我们的研究表明肾小管上皮细胞SnoN蛋白表达减少可能是DN肾纤维化进行性发展的重要因素，但其调控机制仍有待阐明。BMP-7具有对抗TGF-β1致纤维化的效应，然而具体作用机制迄今不甚清楚。其他作者和我们近期的研究提示，恢复内源性SnoN蛋白表达水平可能是BMP-7抗TGF-β1致肾纤维化效应的重要机制。但在DN时，BMP-7调控SnoN表达的具体作用环节和机制尚不清楚。本项目从DN动物模型和高糖培养的肾小管上皮细胞两个体系进行研究，采取基因敲低、激动实验等干预措施，发现BMP-7增加高糖环境中肾小管上皮细胞SnoN蛋白表达的效应不是通过抑制E3泛素连接酶对其的降解，而是上调其mRNA的表达。并进一步明确BMP-7对高糖诱导NRE-52E细胞的表型转化和胶原蛋白Ⅲ的合成有明显抑制作用，其作用机制与BMP-7通过在转录和蛋白水平上调SnoN的蛋白表达，阻断TGF-β/Smads信号通路致纤维化效应有关。这将有助于进一步阐明DN的发病机制，并为DN治疗药物的开发提供新的靶点。