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

Acta Pharmacologica Sinica (2024)Cite this article

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.

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Fig. 1: The IL-6/STAT3 axis mediates expression of the AT2R during liver injury repair and regeneration.
Fig. 2: AT2R deficiency impairs liver regeneration and repair after acute injury in mice.
Fig. 3: The AT2R regulates the Hippo–Yap signaling pathway.
Fig. 4: The Yap pathway is involved in AT2R activation-induced liver growth.
Fig. 5: AT2R activation-induced liver growth is Yap-dependent.
Fig. 6: Gα13 acts as a key mediator of AT2R signaling to modulate the Hippo pathway.
Fig. 7: An AT2R agonist promotes repair and regeneration of liver tissue after acute injury.
Fig. 8: Model showing the proposed mechanisms underlying activation of the AT2R and its role in liver repair and regeneration.

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References

  1. Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol. 2017;27:R1147–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Natarajan A, Wagner B, Sibilia M. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci USA. 2007;104:17081–6.

  3. Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C. Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA. 2004;101:10608–13.

  4. Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24:862–74.

  5. Wu H, Wei L, Fan F, Ji S, Zhang S, Geng J. et al. Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nat Commun. 2015;6:6239.

  6. Gan W, Dai X, Dai X, Xie J, Yin S, Zhu J, et al. LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control. Nat Cell Biol. 2020;22:246–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Han H, Nakaoka HJ, Hofmann L, Zhou JJ, Yu C, Zeng L. et al. The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1. Nat Cell Biol. 2022;24:74–87.

  8. Kim E, Kang JG, Kang MJ, Park JH, Kim YJ, Kweon TH. et al. O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity. Proc Natl Acad Sci USA. 2020;117:14259–69.

  9. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Holden JK, Crawford JJ, Noland CL, Schmidt S, Zbieg JR, Lacap JA, et al. Small molecule dysregulation of TEAD lipidation induces a dominant-negative inhibition of Hippo pathway signaling. Cell Rep. 2020;31:107809.

    Article  CAS  PubMed  Google Scholar 

  11. Rozengurt E, Sinnett-Smith J, Eibl G. Yes-associated protein (YAP) in pancreatic cancer: at the epicenter of a targetable signaling network associated with patient survival. Signal Transduct Target Ther. 2018;3:11.

  12. Yang D, Fu W, Li L, Xia X, Liao Q, Yue R, et al. Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction. Clin Sci. 2017;131:2919–32.

    Article  CAS  Google Scholar 

  13. Gill MK, Christova T, Zhang YY, Gregorieff A, Zhang L, Narimatsu M, et al. A feed forward loop enforces YAP/TAZ signaling during tumorigenesis. Nat Commun. 2018;9:3510.

  14. Mooring M, Fowl BH, Lum S, Liu Y, Yao K, Softic S, et al. Hepatocyte stress increases expression of Yes-associated protein and transcriptional coactivator with PDZ-binding motif in hepatocytes to promote parenchymal inflammation and fibrosis. Hepatology. 2020;71:1813–30.

  15. Ji S, Liu Q, Zhang S, Chen Q, Wang C, Zhang W, et al. FGF15 activates Hippo signaling to suppress bile acid metabolism and liver tumorigenesis. Dev Cell. 2019;48:460–74.

  16. Thomann S, Weiler S, Marquard S, Rose F, Ball CR, Toth M, et al. YAP orchestrates heterotypic endothelial cell communication via HGF/c-MET signaling in liver tumorigenesis. Cancer Res. 2020;80:5502–14.

  17. Nishio M, Sugimachi K, Goto H, Wang J, Morikawa T, Miyachi Y, et al. Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc Natl Acad Sci USA. 2016;113:E71–80.

  18. Liu Y, Lu T, Zhang C, Xu J, Xue Z, Busuttil RW. et al. Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury. J Hepatol. 2019;71:719–30.

  19. Fan F, He Z, Kong LL, Chen Q, Yuan Q, Zhang S, et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med. 2016;8:108r–352r.

    Article  Google Scholar 

  20. Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012;150:780–91.

  21. Lemmens S, Kusters L, Bronckaers A, Geurts N, Hendrix S. The beta2-adrenoceptor agonist terbutaline stimulates angiogenesis via Akt and ERK signaling. J Cell Physiol. 2017;232:298–308.

    Article  CAS  PubMed  Google Scholar 

  22. Tao X, Chen C, Chen Y, Zhang L, Hu J, Yu H, et al. β2-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met. Cell Death Dis. 2022;13:571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shimizu T, Sugiura K, Sakai Y, Dar AR, Butcher RA, Matsumoto K, et al. Chemical signaling regulates axon regeneration via the GPCR-Gqα pathway in Caenorhabditis elegans. J Neurosci. 2022;42:720–30.

  24. Giovanni S, Alessia P, Ece Y, Gaby EA, Maroun BS, Antimo G, et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology. 2020;159:956–68.e8.

    Article  Google Scholar 

  25. Li J, Culman J, Hörtnagl H, Zhao Y, Gerova N, Timm M, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J. 2005;19:617–9.

    Article  CAS  PubMed  Google Scholar 

  26. Rompe F, Artuc M, Hallberg A, Alterman M, Ströder K, Thöne-Reineke C, et al. Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB. Hypertension. 2010;55:924–31.

    Article  CAS  PubMed  Google Scholar 

  27. Schwengel K, Namsolleck P, Lucht K, Clausen BH, Lambertsen KL, Valero-Esquitino V, et al. Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice. J Mol Med. 2016;94:957–66.

    Article  CAS  PubMed  Google Scholar 

  28. Liu Q, Pan S, Liu S, Zhang S, Willerson JT, Martin JF, et al. Suppressing Hippo signaling in the stem cell niche promotes skeletal muscle regeneration. Stem Cells. 2021;39:737–49.

  29. Mitchell C, Willenbring H. A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice. Nat Protoc. 2008;3:1167–70.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang Z, Yao T, Zhao N, Liu H, Cheng H, Gonzalez FJ. et al. Disruption of peroxisome proliferator-activated receptor alpha in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway. Int J Biol Sci. 2022;18:2317–28.

  31. Sun Z, Cade R, Zhang Z, Alouidor J, Van H. Angiotensinogen gene knockout delays and attenuates cold-induced hypertension. Hypertension. 2003;41:322–27.

  32. Zhou YF, Song SS, Tian MX, Tang Z, Wang H, Fang Y, et al. Cystathionine beta-synthase mediated PRRX2/IL-6/STAT3 inactivation suppresses Tregs infiltration and induces apoptosis to inhibit HCC carcinogenesis. J Immunother Cancer. 2021;9:e003031.

  33. Lu X, Wo G, Li B, Xu C, Wu J, Jiang C, et al. The anti-inflammatory NHE-06 restores antitumor immunity by targeting NF-kappaB/IL-6/STAT3 signaling in hepatocellular carcinoma. Biomed Pharmacother. 2018;102:420–27.

    Article  CAS  PubMed  Google Scholar 

  34. Russell JO, Camargo FD. Hippo signalling in the liver: role in development, regeneration and disease. Nat Rev Gastroenterol Hepatol. 2022;19:297–312.

  35. Lu L, Finegold MJ, Johnson RL. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp Mol Med. 2018;50:e423.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lai HS, Lin WH, Lai SL, Lin HY, Hsu WM, Chou CH, et al. Interleukin-6 mediates angiotensinogen gene expression during liver regeneration. PLoS One. 2013;8:e67868.

  37. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379–83.

  38. James LP, Lamps LW, McCullough S, Hinson JA. Interleukin 6 and hepatocyte regeneration in acetaminophen toxicity in the mouse. Biochem Biophys Res Commun. 2003;309:857–63.

    Article  CAS  PubMed  Google Scholar 

  39. Grady EF, Sechi LA, Griffin CA, Schambelan M, Kalinyak JE. Expression of AT2 receptors in the developing rat fetus. J Clin Invest. 1991;88:921–33.

  40. Millan MA, Carvallo P, Izumi S, Zemel S, Catt KJ, Aguilera G. Novel sites of expression of functional angiotensin II receptors in the late gestation fetus. Science. 1989;244:1340–42.

    Article  ADS  CAS  PubMed  Google Scholar 

  41. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal diseases. Circ Res. 1998;83:1182–91.

  42. Ismael S, Ishrat T. Compound 21, a direct AT2R agonist, induces IL-10 and inhibits inflammation in mice following traumatic brain injury. Neuromol Med. 2022;24:274–8.

    Article  CAS  Google Scholar 

  43. Sharma N, Gaikwad AB. Ameliorative effect of AT2R and ACE2 activation on ischemic renal injury associated cardiac and hepatic dysfunction. Environ Toxicol Pharmacol. 2020;80:103501.

    Article  CAS  PubMed  Google Scholar 

  44. Li Y, Xiao D, Yang S, Zhang L. Promoter methylation represses AT2R gene and increases brain hypoxic-ischemic injury in neonatal rats. Neurobiol Dis. 2013;60:32–38.

    Article  CAS  PubMed  Google Scholar 

  45. Kaschina E, Namsolleck P, Unger T. AT2 receptors in cardiovascular and renal diseases. Pharmacol Res. 2017;125:39–47.

    Article  CAS  PubMed  Google Scholar 

  46. Yoshida T, Delafontaine P. An intronic enhancer element regulates angiotensin II type 2 receptor expression during satellite cell differentiation, and its activity is suppressed in congestive heart failure. J Biol Chem. 2016;291:25578–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Laflamme L, Gasparo M, Gallo JM, Payet MD, Gallo-Payet N. Angiotensin II induction of neurite outgrowth by AT2 receptors in NG108-15 cells. Effect counteracted by the AT1 receptors. J Biol Chem. 1996;271:22729–35.

  48. Lucius R, Gallinat S, Rosenstiel P, Herdegen T, Sievers J, Unger T. The angiotensin II type 2 (AT2) receptor promotes axonal regeneration in the optic nerve of adult rats. J Exp Med. 1998;188:661–70.

  49. Curato C, Slavic S, Dong J, Skorska A, Altarche-Xifro W, Miteva K, et al. Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury. J Immunol. 2010;185:6286–93.

  50. Xu XP, Huang LL, Hu SL, Han JB, He HL, Xu JY, et al. Genetic modification of mesenchymal stem cells overexpressing angiotensin II type 2 receptor increases cell migration to injured lung in LPS-induced acute lung injury mice. Stem Cells Transl Med. 2018;7:721–30.

  51. Ali R, Patel S, Hussain T. Angiotensin type 2 receptor activation limits kidney injury during the early phase and induces Treg cells during the late phase of renal ischemia. Am J Physiol Ren Physiol. 2021;320:F814–25.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81871973 to SHZ) and the Basic and Clinical Cooperative Research and Promotion Program of Anhui Medical University (2020xkjT023 to HQ). We are particularly grateful to the Center for Scientific Research of Anhui Medical University for its support. The funders had no role in designing the study, collecting and analyzing the data, deciding to publish, or writing the manuscript.

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  1. These authors contributed equally: Chang-yong Xu, Ji Jiang, Yue An

Authors and 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

    Chang-yong Xu, Ji Jiang, Yue An, Peng-fei Ye, Wen-min Liu, Mei Yang, Wei-hua Zhu, Jing-jing Yu, Man-man Yu, Wu-yi Sun, Shi-hao Zhang & Wei Wei

  2. School of Nursing, Anhui Medical University, Hefei, 230032, China

    Cun-cun Zhang, Ning-ning Sun, Sai-nan Miao, Meng-qi Chai & Huan Qiu

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Contributions

Research concept and design: SHZ, CYX, HQ, WW. Conducting the experiments and data analysis: SHZ, CYX, YA, JJ, PFY, WML, MY, WHZ, JJY, MMY, CCZ, NNS, SNM, WYS, and MQC. Manuscript writing and revising: SHZ and CYX. All authors discussed the data and commented on the manuscript.

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Correspondence to Huan Qiu, Shi-hao Zhang or Wei Wei.

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Xu, Cy., Jiang, J., An, Y. et al. Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01249-0

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