乙酰化KLF4/6和促炎因子启动子上组蛋白调控MsPGN炎性病变的分子机制

人类系膜增生性肾小球肾炎（MsPGN）发病率高，其肾组织免疫炎性病变是医学界难题之一。我们发现，大鼠Thy-1肾炎（MsPGN模型）发病早期，肾组织中有促炎因子（TNF-α、IL-18、MCP-1和Rantes）生成和T细胞及Mφ浸润。鉴于具有乙酰转移酶活性的转录辅激活因子（PCAF）和转录因子（KLF4、KLF6）均是Thy-1肾炎大鼠肾组织和亚溶解型补体攻膜复合物（即sublytic C5b-9）诱导肾小球系膜细胞（GMC）早期明显上调的共表达基因，故为了探讨sublytic C5b-9诱导促炎因子的转录调控机制，本研究拟从体内和体外探索KLF4、KLF6的作用及其PCAF乙酰化修饰这两种转录因子和促炎因子启动子上组蛋白致其染色质重塑后对前述促炎因子基因转录的影响。旨在为揭示Thy-1肾炎生成促炎因子和炎性病变的分子机制（包括表观遗传学调控），并为今后防治人类MsPGN提供科学依据。

Human mesangial proliferative glomerulonephritis (MsPGN) is a disease with high incidence, and the immunologic inflammation leading to damages is a difficult problem of medical research field in the world. Our previous studies demonstrated that the production of pro-inflammatory cytokines (TNF-α, IL-18, MCP-1 and Rantes) and infiltration of inflammatory T cells and macrophages were seen in the renal tissue of rats with Thy-1 nephritis (a model of MsPGN). Given that the transcription coactivator PCAF with acetyltransferase activity and transcriptional factor KLF4 and KLF6 were significantly co-upregulated both in the renal tissue of rat Thy-1 nephritis and in the glomerular mesangial cells (GMC) stimulated with sublytic C5b-9 complex, and in order to elucidate the mechanism of transcriptional regulation on production of the pro-inflammatory cytokines in the GMC upon sublytic C5b-9 stimulation, we attempt to explore the role of KLF4 or KLF6, including the effects of acetylated KLF4 or KLF6 and histone located in promoters of the pro-inflammatory cytokines on the gene transcription of these cytokines. The purpose of our study is to reveal molecular and epigenetic mechanism in the expression of pro-inflammatory cytokines and renal damage in the rat with Thy-1 nephritis, and further to provide an evidence for preventing and treating human MsPGN.