肾源性HMGB1介导的炎症反应在脓毒症AKI向CKD转化中的作用

项目名称： 肾源性HMGB1介导的炎症反应在脓毒症AKI向CKD转化中的作用

项目编号： No.81500516

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈星华

作者单位： 武汉大学

项目金额： 17万元

中文摘要： AKI患者每年25.8%进展到CKD，其风险是不伴AKI人群的8.8倍。肾脏的炎症反应在AKI-CKD转变过程中起重要作用，但调节炎症反应的分子机制不明。我们前期研究发现脓毒症AKI大鼠血液、尿液HMGB1水平升高，脂多糖诱导足细胞分泌HMGB1。因此，本研究推测足细胞、肾小管上皮细胞持续分泌HMGB1介导肾脏炎症反应，诱导脓毒症AKI-CKD的转变。本项目拟采用CLP脓毒症大鼠模型，并以足细胞、肾小管上皮细胞、成纤维细胞系为研究对象，应用基因转染、细胞共培养等手段，观察细胞分泌的HMGB1、其他炎症因子及细胞表型的改变，明确HMGB1通过与RAGE、TLR4、TLR2等受体蛋白相互作用介导炎症反应，诱发肾间质纤维化，深入探讨肾源性HMGB1在脓毒症AKI-CKD转化过程中的作用。本项目的实施将有助于阐明脓毒症AKI慢性化转变的炎症机制，并为脓毒症AKI-CKD转变的防治提供新的思路。

中文关键词： 急性肾损伤；慢性肾脏病；炎症；高迁移率族蛋白B1

英文摘要： Patients with acute kidney disease (AKI) had higher risks of developing chronic kidney disease (CKD) (pooled adjusted hazard ratio 8.8), and the pooled incidence 25.8/100 person-years. The renal inflammatory response plays an important role in the process of AKI to CKD, but the specific molecular mechanism is still unclear. Our team has demonstrated that the serum and urine HMGB1 levels were increased in septic AKI rats, lipopolysaccharide induced cultured podocytes to secrete HMGB1. Therefore, we hypothesizes that continuous HMGB1 secreted by podocytes and renal tubular epithelial cells, mediates renal inflammatory response, which promote chronic transition after septic AKI. This project intends to evaluate the role of HMGB1 in the process of transition from septic AKI to CKD. We will evaluate the secretion of HMGB1, inflammatory factor and the phenotypic changes of the renal cells, we will also evaluate the interaction between HMGB1 and RAGE, TLR4 or TLR2 in the CLP septic rat model and cultured and co-cultured renal cells (podocytes, renal tubular epithelial cells and renal interstitial fibroblasts) treated with plasmid or small hairpin RNA transfection. This study will help us to clarify the molecular mechanism of septic AKI to CKD, and to supply the prevention means.

英文关键词： Acute kidney injury (AKI);Chronic kidney disease (CKD);Inflammation;High mobility group box 1 (HMGB1)