转录因子C/EBPs在肾纤维化过程中的作用及其机制研究

Renal fibrosis is a common consequence of all kidney diseases progressing to ESRD. C/EBPs can regulate cell differentiation and inflammation. It is indicated, by our protein genomics results in samples from patients with different types of primary glomerulonephritis, that C/EBP-alpha was one of the meaningful proteins whose level differs among four groups(control, IgA nephropathy, FSGS and Membranous Nephropathy). Aiming to confirm that C/EBPs can be used as an indicator of the severity of kidne disease in a non-invasive way and its role in renal fibrosis, we plan to test the expression of C/EBPs among serum, urine and kidney tissue from patients with various CKD stages and two animal models(UUO and adriamycin nephropathy) as well. Moreover, we will study the mechanism of C/EBPs in renal fibrosis by TNF-α/IL-1β -stimulated tubular epithelial cells and adriamycin- stimulated podocytes based on transfection, small interfering RNA, EMSA and other techniques. Besides, C/EBP-α knockout mice models(UUO and adriamycin nephropathy) will be chosen to verify C/EBP-α's protecting role in kidney. In all, our study is promising to find a novel biomarker contributing to the early dignosisis of renal fibrosis and establish new therapeutic targets.

肾脏纤维化是各种肾病进展至终末期的共同病理表现。CCAAT增强子结合蛋白（C/EBPs）调节多种的细胞分化及炎症因子表达。前期课题组证实原发性肾小球肾炎患者C/EBP-α水平下降且具有疾病差异性。为进一步探讨C/EBPs作为肾脏疾病严重程度分期的无创指标及其在肾脏纤维化中的作用，本项目拟通过在各期CKD患者血、尿和肾组织及单侧输尿管梗阻（UUO）模型和阿霉素肾病模型验证C/EBPs表达差异，并研究其与肾脏纤维化的关系；通过基因转染、siRNA干扰、EMSA等技术研究TNF-α/IL-1β刺激下肾小管上皮细胞和阿霉素刺激下足细胞C/EBPs参与肾脏纤维化的机制；利用C/EBP-α基因敲除小鼠，观察C/EBP-α对UUO和阿霉素肾病模型的肾脏保护作用，进一步阐明C/EBP-α在肾脏纤维化中作用，为寻找新的干预靶点提供理论依据。

肾脏纤维化是各种肾病进展至终末期的共同病理表现。CCAAT增强子结合蛋白（C/EBPs）调节多种的细胞分化及炎症因子表达。前期课题组证实原发性肾小球肾炎患者C/EBPα水平下降且具有疾病差异性。因此，本课题组进一步探讨C/EBPs在肾脏肾脏纤维化中的作用及机制，本项目通过检测C/EBPα在人肾组织、血尿中的表达及与肾间质纤维化的关系、单侧输尿管梗阻（UUO）模型和阿霉素肾病模型验证C/EBPs表达差异；通过基因调控技术发现TNF-α/IL-1β刺激下肾小管上皮细胞和足细胞C/EBPα通过调控炎症途径参与肾脏纤维化；此外，构建C/EBPα足细胞/肾小管上皮细胞条件性敲除小鼠，并利用此敲除小鼠构建UUO、阿霉素肾病模型和糖尿病肾病模型，发现敲除C/EBPα加重肾脏损伤，故对肾脏损伤具有保护作用，其机制与调控炎症因子相关。本项目完成了C/EBPs，尤其C/EBPα在肾脏纤维化中的作用及机制探索，为改善肾脏纤维化提供理论依据。本课题受资助以来，研究工作顺利，完成了预期结果，发表SCI论文3篇，待发表SCI论文2篇，培养硕士博士6人。