肾小球系膜细胞外基质聚积是糖尿病肾病(DN)进展的重要原因之一，核因子-κB（NF-κB）信号异常与细胞外基质增生密切相关，但DN发生发展中NF-κB活化的机制尚不清楚。本项目提出miRNA在NF-κB异常活化中起关键作用。我们前期工作发现miRNA-451在DN小鼠显著下调，双荧光素酶报告系统和Western blot证实psmb8基因（编码LMP7）是miR-451的靶基因，观察到DN小鼠肾脏组织miR-451表达降低与LMP7高表达同时存在。.我们将研究miR-451通过调节靶基因LMP7的表达，从而影响NF-κB活化，引发一系列细胞因子和趋化因子分泌增强的机理。采用分别上调和下调肾小球系膜细胞中miR-451的表达，研究其对系膜细胞增殖和细胞外基质增生的影响，体外和体内实验研究miR-451对LMP7及NF-κB信号途径中关键分子表达的影响。本研究有助于阐明DN发生的病理生理机制。

Extracellular matrix accumulation of glomerular mesangial cells plays an important role in the development of diabetic nephropathy (DN). NF-κB signals abnormality is closely associated with the accumulation of extracellular matrix. However, the mechanism of NF-κB activity in DN is not fully clear. Here, we emphasized the key role of miRNA in the aberrant activation of NF-κB. Our previous studies found that the expression of miRNA-451 was significantly decreased in the kidney of DN mice by miRNA Microarray Assay. Moreover, we indicated that immunosubunit LMP7 (encoded by psmb8) was a target for miRNA-451 by Dual Glo Luciferase assay and Western blot. More importantly, reduced expression of miRNA-451 and concomitant enhanced expression of LMP7 were observed in the kidney of DN mice..In this project, how miRNA-451 activated NF-κB pathway by targeting of LMP7, and thus, induced an enhanced secretion of cytokine and chemotactic factors, will be discussed. The effect of miR-451 on the proliferation of mesangial cells and deposition of extracellular matrix will be examined by upregulating and downregulating the expression of miR-451. Further, the influence of miRNA-451 on the expression of LMP7 and key signaling molecules in NF-κB pathway in vitro and in vivo will be investigated. The present study may help to elucidate the physiopathological mechanism of DN progression.