冷休克蛋白DbpA调控系膜增生性肾小球肾炎系膜细胞增殖的作用及机制

Abnormal mesangial cells proliferation is the major pathological feature of Mesangioproliferative Glomerulonephritis (MsPGN). To sufficiently analysis and to specifically inhibit this abnormal proliferation is the key factor in research and in the treatment of MsPGN. Our previous studies have shown that the expression of cold shock protein DbpA is closely correlated to mesangial cell proliferation in MsPGN. in vitro experiments confirmed that DbpA significantly promote the proliferation of mesangial cells, suggesting that DbpA is a key factor in the regulation of MsPGN mesangioproliferation. This project is going to establish the MsPGN model with DbpAknock-out mice, through the study of the disease progress with DbpA deletion and with exogenous DbpA complementation, to clarify the effects of DbpA on mesangial cell proliferation in vivo. Further more, we will use the DbpA-/- primary murine mesangial cells, flowing DbpA gene transferring, PDGF-B stimulation and exogenous DbpA intervention. to detect the expression of proliferative factors eg. TK1, PCNA, cyclin, D1 and cyclin A etc. and their related signaling pathways, and to clarify the mechanism. This study is going to provide theoretical and experimental basis for further research in the treatment of MsPGN via targeting DbpA.

系膜细胞的异常增殖是系膜增生性肾小球肾炎（MsPGN）最主要的病理特征，充分解析该增殖机制予以靶向干预是目前MsPGN研究和治疗的关键。我们的前期研究显示冷休克蛋白DbpA在MsPGN系膜细胞中的表达与其增殖程度密切正相关，体外实验证实了其有显著促进系膜细胞增殖的作用，提示DbpA是MsPGN中调控系膜细胞增殖的关键因子。为进一步验证DbpA在体内对系膜细胞增殖的作用，本课题将使用DbpA基因敲除小鼠建立MsPGN疾病模型，明确DbpA缺失以及补偿外源性DbpA对小鼠MsPGN系膜细胞增殖的影响；并采用DbpA-/-小鼠原代培养系膜细胞，研究PDGF-B刺激、外源性DbpA干预、DbpA基因再转入对TK1，PCNA，cyclin D1，cyclin A等增殖因子的表达及相关信号通路的影响，进而阐明其作用机制，为后续以DbpA为靶点治疗MsPGN的研究提供理论及实验依据。

系膜细胞的异常增殖是系膜增生性肾小球肾炎（MsPGN）最主要的病理特征，充分解析该增殖机制予以靶向干预是目前MsPGN研究和治疗的关键。我们的前期研究显示冷休克蛋白DbpA在MsPGN系膜细胞中的表达与其增殖程度密切正相关，体外实验证实了其有显著促进系膜细胞增殖的作用，提示DbpA是MsPGN中调控系膜细胞增殖的关键因子。本项目进一步明确了DbpA促进了系膜细胞增殖的作用，部分介导了PDGF-B刺激系膜细胞增殖的作用；该研究解释了PDGF-B对肾脏系膜细胞增殖的部分作用机制，也为基于干预DbpA来治疗系膜增生型肾小球肾炎提供了实验支持。此外，我们在最常见的MsPGN，IgA肾病患者的尿液样本发现了细胞外DbpA的高表达。细胞外DbpA的表达同样受到PDGF-B的调控，并且其表达水平与体外培养系膜细胞的增殖水平呈正相关。该发现使得DbpA有机会成为一个重要的无创检测生物标志物，用于IgA肾病等MsPGN的诊断及疗效的监测，可能拥有广阔的临床应用前景。本项目额外发现了DbpA在急性肾损伤中的高表达及对肾小管缺血再灌注损伤的保护作用，该研究可能为基于干预DbpA来治疗急性肾小管损伤性肾脏疾病提供了实验支持；目前尚未有相关研究报道，有良好的研究及应用前景。