人系膜增生性肾炎(MsPGN)发病率高，其肾小球内细胞外基质(ECM)降解受抑导致ECM积聚和纤维化是亟待攻克的难题之一。我们发现，Thy-1肾炎大鼠(MsPGN模型)肾组织和亚溶解(sublytic)补体C5b-9刺激的肾小球系膜细胞(GMC)中既有组织金属蛋白酶抑制剂1/3 (TIMP1/3)的表达增加，又有泛素E3连接酶TRAF6和转录因子Sp1的同步上调，且沉默TRAF6或Sp1基因后由sublytic C5b-9诱生的TIMP1/3显著减少。鉴于TIMP1/3可抑制ECM降解，而Sp1本身和Sp1蛋白被翻译后修饰(PTMs)均能影响靶基因的激活，故本课题拟研究Sp1和Sp1被TRAF6 K63位多聚泛素化修饰后调控sublytic C5b-9诱导TIMP1/3基因转录的作用及机制，旨在为揭示Thy-1肾炎促使ECM积聚的关键分子，并为寻找防治人类MsPGN重要靶标提供依据。

Human mesangial proliferative glomerulonephritis (MsPGN) is a disease with high incidence, and the degradation inhibition of glomerular extracellular matrix (ECM) leading to ECM accumulation and kidney fiborosis is a difficult problem in the world. We found that the production of tissue inhibitor of matrix metalloproteinases 1 and 3 (TIMP1/3), ubiquitin E3 ligase TRAF6 and transcriptional factor Sp1 was simultaneously co-upregulated both in the renal tissue of rats with Thy-1 nephritis (a model of MsPGN) and in the glomerular mesangial cells (GMC) stimulated with sublytic C5b-9. Besides, the knockdown of TRAF6 or Sp1 gene could markedly decrease TIMP1/3 synthesis in rat GMC induced by sublytic C5b-9. Given that TIMP1/3 expression could inhibit ECM degradation, and Sp1 or Sp1 post-translational modifications (PTMs) could regulate target gene activation, we attempt to explore the effect and mechanism of Sp1 and Sp1 modification via K63-linked polyubiquitination by TRAF6 on the transcription of TIMP1/3 gene upon sublytic C5b-9 stimulation. The purpose of this study is to reveal some key molecules in the promoting ECM accumulation of rat Thy-1 nephritis, and further to provide evidence for searching important targets of preventing and treating human MsPGN.