Arginase-2下调HO-1表达促进肾小管上皮细胞硝化应激在碘造影剂肾病中的作用及机制研究

碘造影剂肾病（CI-AKI）已成为不可忽视的重要临床问题，但发病机制不明且缺乏有效防治措施。本项目基于前期蛋白质组学和转录组学发现CI-AKI小鼠肾组织中精氨酸酶-2（Arginase-2）高表达，造影剂可显著升高人和小鼠血清Arginase-2水平；Arginase-2抑制剂可改善小鼠肾功能，沉默Arginase-2可缓解造影剂诱导的HK-2细胞硝化应激，提高细胞存活；蛋白质组学和细胞实验结果提示HO-1可能为Arginase-2的下游分子，提出造影剂可能通过上调Arginase-2，进而下调HO-1表达，促进肾小管上皮细胞硝化应激致CI-AKI。本项目拟基于患者和小鼠探讨血清Arginase-2检测在CI-AKI诊断中的价值，并应用CI-AKI小鼠和细胞损伤模型，通过药物处理或基因干预，阐明Arginase-2致CI-AKI的机制，为CI-AKI的诊断及精准防治提供理论基础和科学依据。

Iodine contrast-induced acute kidney injury (CI-AKI) has become an important clinical problem that cannot be ignored, but it lacks effective prevention and treatment measures because its pathogenesis is still unclear. We discovered the expression of Arginase-2 was up-regulated by analyzing the transcriptomics and proteomics datasets of renal tissues from CI-AKI mice, and then found elevated serum levels of Arginase-2 in patients and mice treated with contrast media. Inhibitor of Arginase-2 could ameliorate renal injury in CI-AKI mice, and Arginase-2 silencing could alleviate the contrast media induced nitrosative stress and enhance cell viability of HK-2 cell. The correlation analysis of proteomics and our preliminary results show that expression of HO-1 may be down-regulated by Arginase-2. Therefore, this project puts forward a hypothesis that contrast media may promote the expression of Arginase-2, and then facilitate nitrosative stress in renal tubular epithelial cell through down-regulating HO-1 in CI-AKI. The purpose of this project is to evaluate whether Arginase-2 could be used as a diagnostic biomarker in mice and patients, and then to clarify the mechanism of Arginase-2 facilitated nitrosative stress in the mice and renal tubular epithelial cell CI-AKI model by the methods of drugs and gene interference, which will provide a scientific basis for Arginase-2 as a novel diagnostic biomarker and potential therapeutic target of CI-AKI.