缺血再灌注性急性肾损伤中Klotho水平与炎症的关系及作用机制研究

项目名称： 缺血再灌注性急性肾损伤中Klotho水平与炎症的关系及作用机制研究

项目编号： No.81470918

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 严玉澄

作者单位： 上海交通大学

项目金额： 73万元

中文摘要： 急性肾损伤（AKI）是临床常见危重病，尚缺乏有效治疗手段。Klotho是一种表达在肾小管上皮细胞的抗衰老蛋白，与炎症之间存在双向调节关系。我们前期研究发现，AKI时肾脏Klotho水平显著降低，且伴随炎症的发生。而补充Klotho蛋白可以有效改善肾功能和炎症，提示Klotho在AKI后肾脏炎症的发生发展中起着重要的作用。NF-κB是调控炎症细胞因子表达的关键转录因子，也是AKI的重要靶点。在非肾病中，Klotho可以抑制PI3K/Akt的磷酸化，进一步介导NF-κB信号通路活化。本课题拟通过体内外研究明确Klotho在肾缺血再灌注AKI时的变化及其与炎症和肾损害的关系，采用基因调控手段确定Klotho是否通过抑制PI3K/Akt的活化，进一步抑制RelA (Ser) 536磷酸化，抑制NF-κB的DNA结合及转位而发挥抗炎症作用的。为今后调节Klotho的表达，防治AKI提供理论依据。

中文关键词： 急性肾损伤；炎症反应；Klotho；NF-κB；Akt

英文摘要： Acute kidney injury is a common clinical critical disease, lack of effective therapies. Klotho is an anti-aging protein expressed in renal tubular epithelial cells. There are two ways regulation between Klotho and inflammation. Our previous study found that, Klotho expression in renal was significantly decreased in AKI and associated with inflammation. Supplement of Klotho could effectively protect from renal injury and inflammation, suggesting that Klotho plays an important role in the development of inflammation in AKI. NF-kB is a key transcription factor in the regulation of cytokine expression and an important target of AKI. In the non kidney disease, Klotho could inhibit the phosphorylation of PI3K/Akt,then further mediat NF-kB pathway activation. In this study, we try to identify the relationship of Klotho level with inflammation and renal injury in ischemic reperfusion AKI. We try to determine whether Klotho could anti inflammation by inhibiting the activation of PI3K/Akt，then inhibiting RelA(Ser)536 phosphorylation and further inhibiting NF-kB DNA binding and translocation by means of gene regulation. This study would provide the theoretical information for the prevention and treatment of AKI by regulating Klotho expression in the future.

英文关键词： acute kidney injury;inflammation;Klotho;NF-kB;Akt