张君杰 徐茜 方天明 张丽 周明生

【摘要】 目的：本文探討了Hippo/YAP通路在血管紧张素Ⅱ（AngⅡ）诱导的高血压肾损伤中的作用。方法：研究时间为2018年5月-2019年12月，将18只雄性C57BL/6小鼠随机分为正常对照组、模型组、治疗组（Verteporfin），模型组和治疗组通过植入胶囊渗透压泵连续灌注AngⅡ持续21 d，治疗组从造模后第1天开始，隔天1次，腹腔注射Verteporfin至实验结束。比较各组SBP、尿蛋白/尿肌酐结果，比较各组YAP、P-LATs、纤维化因子[TGF-β1、CTGF及纤维连接蛋白（FN）]、炎症因子（TNF-α、MCP1及IL-1β）蛋白表达量。结果：三组SBP和尿蛋白/尿肌酐结果比较，差异均有统计学意义（P<0.05）。三组肾小球纤维化面积百分比、肾小球硬化面积百分比比较，差异均有统计学意义（P<0.05）。三组YAP、P-LATs蛋白相对表达量比较，差异均有统计学意义（P<0.05）。三组各纤维化因子蛋白相对表达量结果比较，差异均有统计学意义（P<0.05）。三组各炎症因子蛋白相对表达量结果比较，差异均有统计学意义（P<0.05）。结论：AngⅡ诱导的高血压肾损伤存在有Hippo/YAP通路的激活，该通路可能通过介导肾脏的炎症及纤维化引起肾损伤和高血压。

【关键词】 Hippo/YAP通路 高血压 肾损伤

The Role of Hippo/YAP Pathway in Angiotensin Ⅱ-Induced Hypertension and Its Associated Renal Injury/ZHANG Junjie， XU Qian， FANG Tianming， ZHANG Li， ZHOU Mingsheng. //Medical Innovation of China， 2021， 18（05）： 0-024

[Abstract] Objective： To explore the role of the Hippo/YAP pathways in angiotensin Ⅱ （AngⅡ） induced hypertension renal injury. Method： From May 2018 to December 2019， 18 male C57BL/6 mice were randomly divided into normal control group， model group and treatment group （Verteporfin）. In the model group and the treatment group， AngⅡ was continuously perfused by implanting capsule osmotic pump for 21 days. In the Verteporfin treatment group， Verteporfin was injected intraperitoneally every other day， starting from the first day after modeling， until the end of the experiment. SBP and urinary protein/urinary creatinine were compared， the expressions of YAP， P-LATs， TGF-β1， CTGF and Fibronectin （FN）， TNF-α， MCP1 and IL-1β were compared. Result： There were statistically significant differences in SBP and urinary protein/urinary creatinine among the three groups （P<0.05）. There were statistically significant differences in the percentage of glomerular fibrosis area and glomerular sclerosis area among the three groups （P<0.05）. There were statistically significant differences in the relative expression levels of YAP and P-LATs among the three groups （P<0.05）. There were statistically significant differences in the protein expression levels of fibrosis factors among the three groups （P<0.05）. There were statistically significant differences in the relative expression levels of inflammatory cytokines among the three groups （P<0.05）. Conclusion： There is activation of Hippo/YAP pathway in AngⅡ induced hypertensive renal injury， which may cause renal injury and hypertension by mediating renal inflammation and fibrosis.

[Key words] Hippo/YAP pathway Hypertensive Kidney injury

First-authors address： Shenyang Medical College， Shenyang 110000， China

doi：10.3969/j.issn.1674-4985.2021.05.006

高血压是危害人类健康的常见病，可引起心脑肾等靶器官损害。高血压是引起终末期肾病（end stage renal disease， ESRD）的一个最主要危险因素[1]。高血压肾病的主要病理特征包括肾脏炎症，肾小球基底膜增厚、硬化，肾小球及间质纤维化[2]。高血压肾病发病机制十分复杂，尽管进行了深入的研究，但其发病机制目前尚未完全阐明[3-4]。

近期研究发现一些心血管和肾脏疾病的发生可能与改变Hippo/YAP信号通路有关[5-6]。Hippo通路是在进化过程中高度保守的信号通路，Yes-associated protein（YAP）是一个生物转录调控因子，参与调控组织生长，协调细胞增殖、死亡和分化等[7]，该通路早期研究主要集中在抗肿瘤领域[5]。目前有关该通路在肾脏中的作用所知甚少，近年来备受关注，最新研究提示Hippo/YAP通路参与肾小球和下尿道胚胎发育中的信号传导，维持肾脏足细胞稳态平衡以及肾小球滤过屏障的完整性[8-10]。改变肾脏Hippo/YAP信号通路可能与一些肾脏疾病的发生，如糖尿病肾上皮损伤和肾脏纤维化发生等有关[8]。……