安徽医科大学Wei Wei等研究人员合作发现，血管紧张素II型2受体信号通过抑制Hippo通路促进肝损伤修复和再生。2024年3月15日，《中国药理学报》在线发表了这项成果。

研究人员发现血管紧张素II型2受体（AT2R）可通过使Hippo信号失活来促进急性损伤后的肝脏修复和再生，白细胞介素-6可通过STAT3作为转录激活因子与AT2R的启动子区域结合，转录上调AT2R在肝细胞中的表达。随后，升高的AT2R水平通过异三聚G蛋白Gα12/13偶联信号激活下游信号，诱导Yap活性，从而促进肝脏的修复和再生过程。

相反，缺乏AT2R会减弱肝脏的再生能力，同时增加对乙酰氨基酚引起的肝损伤的易感性。施用AT2R激动剂可显著增强损伤肝组织的修复和再生能力。这些研究结果表明，AT2R是Hippo通路的上游调节因子，是治疗肝损伤的潜在靶点。

据介绍，AT2R是肾素-血管紧张素系统的一个公认的组成部分，已知它能抵消该系统的经典激活并防止器官损伤。药理激活AT2R具有显著的治疗效果，包括扩张血管、利尿、抗炎和改善胰岛素敏感性。然而，AT2R在维持肝组织稳态方面的确切生物功能在很大程度上仍未得到探索。

附：英文原文

Title: Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway

Author: Xu, Chang-yong, Jiang, Ji, An, Yue, Ye, Peng-fei, Zhang, Cun-cun, Sun, Ning-ning, Miao, Sai-nan, Chai, Meng-qi, Liu, Wen-min, Yang, Mei, Zhu, Wei-hua, Yu, Jing-jing, Yu, Man-man, Sun, Wu-yi, Qiu, Huan, Zhang, Shi-hao, Wei, Wei

Issue&Volume: 2024-03-15

Abstract: The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.

DOI: 10.1038/s41401-024-01249-0

Source: https://www.nature.com/articles/s41401-024-01249-0