β2-AR/PKA通路在内皮祖细胞修复急性肾损伤中的作用及机制

The incidence of acute kidney injury(AKI) increases yearly, and this disease could lead to chronic kidney disease, with high mortality, while there is no effective treatment for it. Vascular endothelial injury is critical in the pathogenesis of AKI . Several studies demonstrated that endothelial progenitor cells (EPCs) may improve renal microenvironment, stimulate endothelial repair and angiogenesis, and promote AKI restoration. However, the molecular mechanism has not been elucidated, which limited its clinical application. β2 adrenergic receptor (β2-AR) is a newly discovered receptor on surface of EPCs, and plays a key role in the treatment of EPCs to hindlimb ischemia in animal model. Protein kinase A(PKA), as a regulator downstream of β2-AR, is closely associated with cell growth and proliferation. We guess β2-AR/PKA pathway may regulate EPCs in the restoration of AKI, and our preliminary research showed that, transcriptional activity of β2-AR and PKA increase in the renal tissue while kidney repairing. We plan to do the research in vitro and in vivo to explore the role of β2-AR/PKA signaling pathway in the repair of ischemic AKI by EPCs. Comprehending deeply of this signal pathway will understand the mechanism of renal repair and then direct research and development of specific targeted drugs.

急性肾损伤（AKI）在我国发病率逐年递增，可发展为慢性肾脏疾病，死亡率高，目前尚无有效的病因治疗手段。血管内皮损伤是AKI的关键发病机制。大量研究证实，内皮祖细胞（EPCs）可分泌细胞因子改善肾脏微环境，促进内皮修复和血管生成，促进AKI修复；但目前分子机制尚未阐明，从而限制了临床应用。β2肾上腺素受体（β2-AR）是新近发现的EPCs表面受体，动物实验提示EPCs治疗后肢缺血时，β2-AR起关键作用。蛋白激酶A（PKA）是β2-AR的下游信号调节因子之一，与细胞的生长和增殖等密切相关。我们猜测β2-AR/PKA通路可调控EPCs修复AKI，且预实验发现，AKI修复期肾组织内β2-AR及PKA转录活性增加。本研究拟通过动物模型和细胞实验，探讨β2-AR/PKA信号通路在EPCs修复缺血性AKI中的作用。本研究有助于明确EPCs修复AKI的分子机制，为寻找AKI新的治疗靶点提供理论依据。

项目背景. . 4型CRS，也被称为慢性肾心综合征，主要特征是慢性肾功能不全引起心功能损害。. 目前对于4型CRS的预后研究尚不多，本研究旨在通过回顾性研究，分析4型CRS患者1年内预后的预测因子。..主要研究内容. 回顾性分析上海市同济医院2015年1月至2015年12月的内科住院患者，其中发生4型心肾综合征者共105例，搜集患者的临床病史资料以及生化检验指标，同时统计这些患者到2016年底的死亡率，比较存活组和死亡组的各项指标，通过Logistic回归分析1年死亡的预后因素。..重要结果. 105例4型CRS患者中，男性为60例，占57.1%，年龄72.67±12.07岁，其中1年内死亡12例；Logistic回归多因素分析提示，BNP、Na浓度可独立预测4型心肾综合征患者的1年内死亡。..关键数据及其科学意义. 多因素Logistic回归分析..B. S.E.Wald. P.OR.na.-0.165.0.077. 4.617.0.032. 0.848.bnp.0.001. 0.000. 4.671.0.031 1.001.sex.0.287. 0.793. 0.131.0.717 1.333.age.0.053. 0.034. 2.454.0.117 1.054