AR/miRNA-21在肾缺血再灌注损伤性别差异表达的调控研究

Renal ischemia-reperfusion injury (IRI) is one of the important cause of acute renal failure. Our previous studies have found that male mice was more sensitive to renal IRI than females, further study showed that the expression of androgen receptor (AR) and miR - 21 in kidney tissue of male mice after ischemia was lower than that of female mice. Also, studies have shown that the expression of AR and miR - 21 in prostate tissue developed positive feedback loop. So, we propose the hypothesis: AR regulating miR - 21 may play a key role in the gender differences of renal IRI . This project will explore interaction control of AR/miR - 21 signal in different gender in different stages of renal ischemia injury in mice and the regulation role of PDCD4 target genes and apoptosis proteins caspase-3, by anoxia and reoxygenation model of renal tubular epithelial cells and kidney IRI model in mice, from the molecules, cells, tissues and overall level of the animals. In order to illustrate the possible mechanism of the different expression of miR-21 in gender differences of renal IRI, and observe the change of sensitivity to the renal ischemia injury in mice and the change of apoptosis of renal tubular epithelial cells by intervening in AR/miR - 21 signal. In order to find the possible mechanism of gender differences in renal IRI.

肾缺血再灌注损伤（IRI）是引起急性肾功能衰竭的重要原因之一。我们前期研究发现雄性小鼠比雌性小鼠对肾IRI更敏感，进一步研究表明：雄激素受体（AR）与miR-21在雄性小鼠缺血后肾组织中的表达明显低于雌性小鼠。而且，有研究表明AR与miR-21在前列腺组织中表达存在正反馈环。为此，我们提出假说：AR调控miR-21可能在肾IRI性别差异中起关键作用。本项目将通过小鼠肾小管上皮细胞缺氧复氧模型和小鼠肾IRI模型，从分子、细胞、组织及动物整体水平探讨AR/miR-21信号在不同性别的小鼠肾缺血损伤不同阶段中的相互调控作用以及对miR-21靶基因PDCD4和凋亡蛋白caspase-3等的调控作用，阐明肾IRI中miR-21性别差异表达的可能机制，并通过干预AR/miR-21信号观察小鼠对肾缺血损伤的敏感性的变化和肾小管上皮细胞凋亡的变化。以期寻找肾IRI性别差异的可能机制。

本研究通过建立小鼠肾小管上皮细胞TCMK-1缺氧复氧模型和小鼠肾缺血再灌注损伤模型，从分子、细胞、组织及动物整体水平探讨 AR/miR-21信号轴在不同性别的小鼠肾缺血再灌注损伤中的相互调控作用以及对 miR-21靶基因 PDCD4 和凋亡蛋白 caspase-3 等的调控作用，阐明肾 IRI 性别差异的可能机制，并通过干预 AR/miR-21 信号轴观察小鼠对肾缺血再灌注损伤的敏感性的变化和肾小管上皮细胞凋亡的变化。主要结果：1.肾缺血再灌注导致肾组织miR-21表达升高，AR表达降低；2.过表达miR-21能减少TCMK-1细胞缺氧复氧损伤，并减轻小鼠肾缺血再灌注损伤；3.干扰miR-21会加重TCMK-1细胞缺氧复氧损伤，并加重小鼠肾缺血再灌注损伤；4.干扰雄激素受体AR使其降低可以加重TCMK-1细胞缺氧复氧损伤，加重小鼠肾缺血再灌注损伤；5.过表达miR-21会使AR升高，干扰miR-21会使AR降低，干扰AR会使miR-21降低。AR/miR-21信号轴对肾缺血再灌注损伤性别差具有调控作用，AR和miR-21两者之间可能存在一定的正反馈关系。相比雌性小鼠，雄性小鼠对于AR受体的降低更为敏感，肾缺血再灌注损伤更严重。AR/miR-21信号可能是治疗肾缺血再灌注损伤的重要靶点。