SpringerLink
Log in

β-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/β-catenin signaling in mice

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Despite substantial progress being made in understanding the mechanisms contributing to the pathogenesis of renal fibrosis, there are only a few therapies available to treat or prevent renal fibrosis in clinical use today. Therefore, identifying the key cellular and molecular mediators involved in the pathogenesis of renal fibrosis will provide new therapeutic strategy for treating patients with chronic kidney disease (CKD). β-Arrestin-1, a member of β-arrestin family, not only is a negative adaptor of G protein-coupled receptors (GPCRs), but also acts as a scaffold protein and regulates a diverse array of cellular functions independent of GPCR activation. In this study, we identified for the first time that β-arrestin-1 was upregulated in the kidney from mice with unilateral ureteral obstruction nephropathy as well as in the paraffin-embedded sections of human kidneys from the patients with diabetic nephropathy, polycystic kidney, or uronephrosis, which normally causes renal fibrosis. Deficiency of β-arrestin-1 in mice significantly alleviated renal fibrosis by the regulation of inflammatory responses, kidney fibroblast activation, and epithelial-mesenchymal transition (EMT) in both in vivo and in vitro studies. Furthermore, we found that among the major isoforms of Wnts, Wnt1 was regulated by β-arrestin-1 and gene silencing of Wnt1 inhibited the activation of β-catenin and suppressed β-arrestin-1-mediated renal fibrosis. Collectively, our results indicate that β-arrestin-1 is one of the critical components of signal transduction pathways in the development of renal fibrosis. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with renal fibrosis.

Key messages

  • β-Arrestin-1 was upregulated in the kidney from mice with UUO nephropathy.

  • β-Arrestin-1 regulated kidney fibroblast activation and epithelial-mesenchymal transition.

  • β-Arrestin-1 exacerbated renal fibrosis via mediating Wnt1/β-catenin signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Zeisberg M, Neilson EG (2010) Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 21:1819–1834

    Article  CAS  PubMed  Google Scholar 

  2. Boor P, Ostendorf T, Floege J (2010) Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol 6:643–656

    Article  PubMed  Google Scholar 

  3. Pupo AS, Duarte DA, Lima V, Teixeira LB, Parreiras ESLT, Costa-Neto CM (2016) Recent updates on GPCR biased agonism. Pharmacol Res 112:49–57

    Article  CAS  PubMed  Google Scholar 

  4. Kamal FA, Travers JG, Schafer AE, Ma Q, Devarajan P, Blaxall BC (2017) G protein-coupled receptor-G-protein beta gamma-subunit signaling mediates renal dysfunction and fibrosis in heart failure. J Am Soc Nephrol 28:197–208

    Article  PubMed  Google Scholar 

  5. Kang DS, Tian X, Benovic JL (2014) Role of beta-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 27:63–71

    Article  PubMed  Google Scholar 

  6. Spiegel A (2003) Cell Signaling. Beta-arrestin—not just for G protein-coupled receptors. Science 301:1338–1339

    Article  CAS  PubMed  Google Scholar 

  7. Kendall RT, Luttrell LM (2009) Diversity in arrestin function. Cell Mol Life Sci 66:2953–2973

    Article  CAS  PubMed  Google Scholar 

  8. Ma L, Pei G (2007) Beta-arrestin signaling and regulation of transcription. J Cell Sci 120:213–218

    Article  CAS  PubMed  Google Scholar 

  9. Quack I, Rump LC, Gerke P, Walther I, Vinke T, Vonend O, Grunwald T, Sellin L (2006) Beta-arrestin2 mediates nephrin endocytosis and impairs slit diaphragm integrity. Proc Natl Acad Sci U S A 103:14110–14115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Quack I, Woznowski M, Potthoff SA, Palmer R, Konigshausen E, Sivritas S, Schiffer M, Stegbauer J, Vonend O, Rump LC et al (2011) PKC alpha mediates beta-arrestin2-dependent nephrin endocytosis in hyperglycemia. J Biol Chem 286:12959–12970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Buelli S, Rosano L, Gagliardini E, Corna D, Longaretti L, Pezzotta A, Perico L, Conti S, Rizzo P, Novelli R et al (2014) Beta-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury. J Am Soc Nephrol 25:523–533

    Article  CAS  PubMed  Google Scholar 

  12. Liu H, Yi F, Yang H (2016) Adaptive grou** cloud model shuffled frog lea** algorithm for solving continuous optimization problems. Comput Intell Neurosci 2016:5675349

  13. Lovgren AK, Kovacs JJ, **e T, Potts EN, Li Y, Foster WM, Liang J, Meltzer EB, Jiang D, Lefkowitz RJ et al (2011) Beta-arrestin deficiency protects against pulmonary fibrosis in mice and prevents fibroblast invasion of extracellular matrix. Sci Transl Med 3:74ra23

    Article  PubMed  PubMed Central  Google Scholar 

  14. YJ G, Sun WY, Zhang S, JJ W, Wei W (2015) The emerging roles of beta-arrestins in fibrotic diseases. Acta Pharmacol Sin 36:1277–1287

    Article  Google Scholar 

  15. Hara MR, Kovacs JJ, Whalen EJ, Rajagopal S, Strachan RT, Grant W, Towers AJ, Williams B, Lam CM, **ao K et al (2011) A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 477:349–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang HM, Dong JH, Li Q, Hu Q, Ning SL, Zheng W, Cui M, Chen TS, **e X, Sun JP et al (2014) A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and beta-arrestin 1. Diabetologia 57:1899–1910

    Article  CAS  PubMed  Google Scholar 

  17. Ai J, Nie J, He J, Guo Q, Li M, Lei Y, Liu Y, Zhou Z, Zhu F, Liang M et al (2015) GQ5 hinders renal fibrosis in obstructive nephropathy by selectively inhibiting TGF-beta-induced Smad3 phosphorylation. J Am Soc Nephrol 26:1827–1838

    Article  CAS  PubMed  Google Scholar 

  18. Du P, Fan B, Han H, Zhen J, Shang J, Wang X, Li X, Shi W, Tang W, Bao C et al (2013) NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int 84:265–276

    Article  CAS  PubMed  Google Scholar 

  19. Yan Y, Ma L, Zhou X, Ponnusamy M, Tang J, Zhuang MA, Tolbert E, Bayliss G, Bai J, Zhuang S (2016) Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int 89:68–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ding Y, Kim S, Lee SY, Koo JK, Wang Z, Choi ME (2014) Autophagy regulates TGF-beta expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J Am Soc Nephrol 25:2835–2846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang Z, Wei X, Zhang Y, Ma X, Li B, Zhang S, Du P, Zhang X, Yi F (2009) NADPH oxidase-derived ROS contributes to upregulation of TRPC6 expression in puromycin aminonucleoside-induced podocyte injury. Cell Physiol Biochem 24:619–626

    Article  CAS  PubMed  Google Scholar 

  22. Yi F, Zhang AY, Janscha JL, Li PL, Zou AP (2004) Homocysteine activates NADH/NADPH oxidase through ceramide-stimulated Rac GTPase activity in rat mesangial cells. Kidney Int 66:1977–1987

    Article  CAS  PubMed  Google Scholar 

  23. Wang X, Liu J, Zhen J, Zhang C, Wan Q, Liu G, Wei X, Zhang Y, Wang Z, Han H et al (2014) Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int 86:712–725

    Article  CAS  PubMed  Google Scholar 

  24. Zhou M, Tang W, Fu Y, Xu X, Wang Z, Lu Y, Liu F, Yang X, Wei X, Zhang Y et al (2015) Progranulin protects against renal ischemia/reperfusion injury in mice. Kidney Int 87:918–929

    Article  CAS  PubMed  Google Scholar 

  25. Kovacs JJ, Hara MR, Davenport CL, Kim J, Lefkowitz RJ (2009) Arrestin development: emerging roles for beta-arrestins in developmental signaling pathways. Dev Cell 17:443–458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Conner DA, Mathier MA, Mortensen RM, Christe M, Vatner SF, Seidman CE, Seidman JG (1997) Beta-arrestin1 knockout mice appear normal but demonstrate altered cardiac responses to beta-adrenergic stimulation. Circ Res 81:1021–1026

    Article  CAS  PubMed  Google Scholar 

  27. Zhou X, Fukuda N, Matsuda H, Endo M, Wang X, Saito K, Ueno T, Matsumoto T, Matsumoto K, Soma M et al (2013) Complement 3 activates the renal renin-angiotensin system by induction of epithelial-to-mesenchymal transition of the nephrotubulus in mice. Am J Phys Renal Phys 305:F957–F967

    CAS  Google Scholar 

  28. Duffield JS (2014) Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest 124:2299–2306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kriz W, Kaissling B, Le Hir M (2011) Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? J Clin Invest 121:468–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Freedman NJ, Shenoy SK (2017) Regulation of inflammation by beta-arrestins: not just receptor tales. Cell Signal. https://doi.org/10.1016/j.cellsig.2017.02.008

  31. Barlic J, Andrews JD, Kelvin AA, Bosinger SE, DeVries ME, Xu L, Dobransky T, Feldman RD, Ferguson SS, Kelvin DJ (2000) Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI. Nat Immunol 1:227–233

    Article  CAS  PubMed  Google Scholar 

  32. Walker JK, Fong AM, Lawson BL, Savov JD, Patel DD, Schwartz DA, Lefkowitz RJ (2003) Beta-arrestin-2 regulates the development of allergic asthma. J Clin Invest 112:566–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Clevers H, Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149:1192–1205

    Article  CAS  PubMed  Google Scholar 

  34. Zhou L, Li Y, Hao S, Zhou D, Tan RJ, Nie J, Hou FF, Kahn M, Liu Y (2014) Multiple genes of the renin-angiotensin system are novel targets of Wnt/beta-catenin signaling. J Am Soc Nephrol 26(1):107–120

    Article  PubMed  PubMed Central  Google Scholar 

  35. He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 20:765–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu J, Li QX, Wang XJ, Zhang C, Duan YQ, Wang ZY, Zhang Y, Yu X, Li NJ, Sun JP et al (2016) Beta-arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy. Cell Death Dis 7:e2183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maarouf OH, Aravamudhan A, Rangarajan D, Kusaba T, Zhang V, Welborn J, Gauvin D, Hou X, Kramann R, Humphreys BD (2016) Paracrine Wnt1 drives interstitial fibrosis without inflammation by tubulointerstitial cross-talk. J Am Soc Nephrol 27:781–790

    Article  CAS  PubMed  Google Scholar 

  38. Chen W, LA H, Semenov MV, Yanagawa S, Kikuchi A, Lefkowitz RJ, Miller WE (2001) Beta-arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins. Proc Natl Acad Sci U S A 98:14889–14894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Qian C, Liu F, Ye B, Zhang X, Liang Y, Yao J (2015) Notch4 promotes gastric cancer growth through activation of Wnt1/beta-catenin signaling. Mol Cell Biochem 401:165–174

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Science Fund for Distinguished Young Scholars to Yi F (81525005) and the National Nature Science Foundation of China (91642204, 81470958, 81371317, 81600570, and 81400730).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Shandong University School of Medicine, #44, Wenhua ** Road, **an, 250012, Shandong, People’s Republic of China

    Huiyan Xu, Quanxin Li, Jiang Liu, Jiaqing Zhu, Liang Li, Ziying Wang, Yan Zhang, Yu Sun & Fan Yi

  2. Department of Nephrology, Shandong Provincial Hospital Affiliated with Shandong University, **an, 250021, China

    Huiyan Xu & Rong Wang

  3. Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, **an, 250012, China

    **peng Sun

  4. The State Key Laboratory of Microbial Technology, Shandong University, **an, 250100, China

    Fan Yi

Authors
  1. Huiyan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Quanxin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiaqing Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ziying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. **peng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fan Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

In this manuscript, Huiyan Xu conducted the experiment, interpreted the data and wrote the manuscript. Quanxin Li, Jiang Liu, Jiaqing Zhu, Liang Li conducted the experiment and analyzed the data. Wang ZY, Zhang Y, Yu Sun, **peng Sun and Rong Wang assisted with the conduction of the experiment. Yi F designed the experiment, wrote the manuscript and approved the final version of the manuscript for publication.

Corresponding author

Correspondence to Fan Yi.

Ethics declarations

All mice had unrestricted access to food/water in accordance with Institutional Animal Care and Use Committee procedures of Shandong University. The investigation conforms to the US National Institutes of Health Guide for the Care and Use of Laboratory Animals. Human renal biopsies were conducted in accordance with the principles of the Declaration of Helsinki and were approved by the Research Ethics Committee of Shandong University after informed consent was obtained from the patients.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, H., Li, Q., Liu, J. et al. β-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/β-catenin signaling in mice. J Mol Med 96, 97–109 (2018). https://doi.org/10.1007/s00109-017-1606-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-017-1606-5

Keywords

Search

Navigation