Hippo-YAP/MCP-1 Mediated Tubular Maladaptive Repair Promote Inflammation in Renal Failed Recovery After Ischemic AKI

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Jul 31

PMID 34330891

Citations 27

Authors

Zhihuang Zheng

Chuanlei Li

Guangze Shao

Jinqing Li

Kexin Xu

Zhonghua Zhao

Zhigang Zhang

Jun Liu

Huijuan Wu

Affiliations

Soon will be listed here.

Abstract

Acute kidney injury (AKI) is associated with significant morbidity and its chronic inflammation contributes to subsequent chronic kidney disease (CKD) development. Yes-associated protein (YAP), the major transcriptional coactivator of the Hippo pathway, has been shown associated with chronic inflammation, but its role and mechanism in AKI-CKD transition remain unclear. Here we aimed to investigate the role of YAP in AKI-induced chronic inflammation. Renal ischemia/reperfusion (I/R) was used to induce a mouse model of AKI-CKD transition. We used verteporfin (VP), a pharmacological inhibitor of YAP, to treat post-IRI mice for a period, and evaluated the influence of YAP inhibition on long-term outcomes of AKI. In our results, severe IRI led to maladaptive tubular repair, macrophages infiltration, and progressive fibrosis. Following AKI, the Hippo pathway was found significantly altered with YAP persistent activation. Besides, tubular YAP activation was associated with the maladaptive repair, also correlated with interstitial macrophage infiltration. Monocyte chemoattractant protein 1 (MCP-1) was found notably upregulated with YAP activation. Of note, pharmacological inhibition of YAP in vivo attenuated renal inflammation, including macrophage infiltration and MCP-1 overexpression. Consistently, in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) induced YAP activation and MCP-1 overproduction whereas these could be inhibited by VP. In addition, we modulated YAP activity by RNA interference, which further confirmed YAP activation enhances MCP-1 expression. Together, we concluded tubular YAP activation with maladaptive repair exacerbates renal inflammation probably via promoting MCP-1 production, which contributes to AKI-CKD transition.

Citing Articles

THBS1 in macrophage-derived exosomes exacerbates cerebral ischemia-reperfusion injury by inducing ferroptosis in endothelial cells.

Liu C, Sui H, Li Z, Sun Z, Li C, Chen G J Neuroinflammation. 2025; 22(1):48.

PMID: 39994679 PMC: 11854006. DOI: 10.1186/s12974-025-03382-x.

Tetramethylpyrazine attenuates sodium arsenite-induced acute kidney injury by improving the autophagic flux blockade via a YAP1-Nrf2-p62-dependent mechanism.

Song Z, Hei T, Gong X Int J Biol Sci. 2025; 21(3):1158-1173.

PMID: 39897028 PMC: 11781175. DOI: 10.7150/ijbs.104107.

HIF-1α mediates hypertension and vascular remodeling in sleep apnea via hippo-YAP pathway activation.

Zhang S, Zhao Y, Dong Z, Jin M, Lu Y, Xu M Mol Med. 2024; 30(1):281.

PMID: 39732653 PMC: 11681631. DOI: 10.1186/s10020-024-00987-5.

Selenium nanoparticles alleviate renal ischemia/reperfusion injury by inhibiting ferritinophagy via the XBP1/NCOA4 pathway.

Zuo Z, Luo M, Liu Z, Liu T, Wang X, Huang X Cell Commun Signal. 2024; 22(1):376.

PMID: 39061070 PMC: 11282718. DOI: 10.1186/s12964-024-01751-2.

Knockout of integrin αvβ6 protects against renal inflammation in chronic kidney disease by reduction of pro-inflammatory macrophages.

Zhu C, Zheng R, Han X, Tang Z, Li F, Hu X Cell Death Dis. 2024; 15(6):397.

PMID: 38844455 PMC: 11156928. DOI: 10.1038/s41419-024-06785-5.

References

Kong W, Haschler T, Nurnberg B, Kramer S, Gollasch M, Marko L . Renal Fibrosis, Immune Cell Infiltration and Changes of TRPC Channel Expression after Unilateral Ureteral Obstruction in Trpc6-/- Mice. Cell Physiol Biochem. 2019; 52(6):1484-1502. DOI: 10.33594/000000103. View

Hwang S, Jin M, Shin Y, Choi S, Namkoong E, Kim M . Role of LPA and the Hippo pathway on apoptosis in salivary gland epithelial cells. Exp Mol Med. 2014; 46:e125. PMC: 4274396. DOI: 10.1038/emm.2014.77. View

Ma B, Cheng H, Gao R, Mu C, Chen L, Wu S . Zyxin-Siah2-Lats2 axis mediates cooperation between Hippo and TGF-β signalling pathways. Nat Commun. 2016; 7:11123. PMC: 4821889. DOI: 10.1038/ncomms11123. View

Mooring M, Fowl B, Lum S, Liu Y, Yao K, Softic S . Hepatocyte Stress Increases Expression of Yes-Associated Protein and Transcriptional Coactivator With PDZ-Binding Motif in Hepatocytes to Promote Parenchymal Inflammation and Fibrosis. Hepatology. 2019; 71(5):1813-1830. PMC: 7062580. DOI: 10.1002/hep.30928. View

Huen S, Cantley L . Macrophages in Renal Injury and Repair. Annu Rev Physiol. 2017; 79:449-469. DOI: 10.1146/annurev-physiol-022516-034219. View

Lin M, Ling J, Geng X, Zhang J, Du J, Chen L . RTN1-C is involved in high glucose-aggravated neuronal cell subjected to oxygen-glucose deprivation and reoxygenation injury via endoplasmic reticulum stress. Brain Res Bull. 2019; 149:129-136. DOI: 10.1016/j.brainresbull.2019.04.010. View

Deshmane S, Kremlev S, Amini S, Sawaya B . Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009; 29(6):313-26. PMC: 2755091. DOI: 10.1089/jir.2008.0027. View

Yang L, Besschetnova T, Brooks C, Shah J, Bonventre J . Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010; 16(5):535-43, 1p following 143. PMC: 3928013. DOI: 10.1038/nm.2144. View

Hagenbeek T, Webster J, Kljavin N, Chang M, Pham T, Lee H . The Hippo pathway effector TAZ induces TEAD-dependent liver inflammation and tumors. Sci Signal. 2018; 11(547). DOI: 10.1126/scisignal.aaj1757. View

10.

Kim W, Khan S, Liu Y, Xu R, Park O, He Y . Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut. 2017; 67(9):1692-1703. PMC: 6592016. DOI: 10.1136/gutjnl-2017-314061. View

11.

Liu B, Tang T, Lv L, Lan H . Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int. 2018; 93(3):568-579. DOI: 10.1016/j.kint.2017.09.033. View

12.

Choi I, Yan H, Park Y, Kim W . Sauchinone reduces oxygen-glucose deprivation-evoked neuronal cell death via suppression of intracellular radical production. Arch Pharm Res. 2010; 32(11):1599-606. DOI: 10.1007/s12272-009-2113-1. View

13.

Devarajan P . Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol. 2006; 17(6):1503-20. DOI: 10.1681/ASN.2006010017. View

14.

Hsu C . Yes, AKI truly leads to CKD. J Am Soc Nephrol. 2012; 23(6):967-9. DOI: 10.1681/ASN.2012030222. View

15.

Sato Y, Takahashi M, Yanagita M . Pathophysiology of AKI to CKD progression. Semin Nephrol. 2020; 40(2):206-215. DOI: 10.1016/j.semnephrol.2020.01.011. View

16.

Li L, Zhou J, Li Q, Xu J, Qi J, Bian H . The inhibition of Hippo/Yap signaling pathway is required for magnesium isoglycyrrhizinate to ameliorate hepatic stellate cell inflammation and activation. Biomed Pharmacother. 2018; 106:83-91. DOI: 10.1016/j.biopha.2018.06.102. View

17.

Bucaloiu I, Kirchner H, Norfolk E, Hartle 2nd J, Perkins R . Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney Int. 2011; 81(5):477-85. DOI: 10.1038/ki.2011.405. View

18.

Gu Y, Huang F, Wang Y, Chen C, Wu S, Zhou S . Connexin32 plays a crucial role in ROS-mediated endoplasmic reticulum stress apoptosis signaling pathway in ischemia reperfusion-induced acute kidney injury. J Transl Med. 2018; 16(1):117. PMC: 5935959. DOI: 10.1186/s12967-018-1493-8. View

19.

Basile D, Bonventre J, Mehta R, Nangaku M, Unwin R, Rosner M . Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments. J Am Soc Nephrol. 2015; 27(3):687-97. PMC: 4769207. DOI: 10.1681/ASN.2015030309. View

20.

Song K, Kwon H, Han C, Chen W, Zhang J, Ma W . Yes-Associated Protein in Kupffer Cells Enhances the Production of Proinflammatory Cytokines and Promotes the Development of Nonalcoholic Steatohepatitis. Hepatology. 2019; 72(1):72-87. PMC: 7153981. DOI: 10.1002/hep.30990. View