1. Academic Validation
  2. Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway

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

  • Acta Pharmacol Sin. 2024 Mar 15. doi: 10.1038/s41401-024-01249-0.
Chang-Yong Xu # 1 Ji Jiang # 1 Yue An # 1 Peng-Fei Ye 1 Cun-Cun Zhang 2 Ning-Ning Sun 2 Sai-Nan Miao 2 Meng-Qi Chai 2 Wen-Min Liu 1 Mei Yang 1 Wei-Hua Zhu 1 Jing-Jing Yu 1 Man-Man Yu 1 Wu-Yi Sun 1 Huan Qiu 3 Shi-Hao Zhang 4 Wei Wei 5
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China.
  • 2 School of Nursing, Anhui Medical University, Hefei, 230032, China.
  • 3 School of Nursing, Anhui Medical University, Hefei, 230032, China. huanqiu@ahmu.edu.cn.
  • 4 Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China. shihaozhang@ahmu.edu.cn.
  • 5 Institute of Clinical Pharmacology, Anhui Medical University; Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China. wwei@ahmu.edu.cn.
  • # Contributed equally.
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.

Keywords

Hippo pathway; Yap; angiotensin II type 2 receptor; liver injury; liver regeneration.

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