Abstract
Acute kidney injury (AKI) refers to a group of common clinical syndromes characterized by acute renal dysfunction, which may lead to chronic kidney disease (CKD), and this process is called the AKI-CKD transition. The transcriptional coactivator YAP can promote the AKI-CKD transition by regulating the expression of profibrotic factors, and 14-3-3 protein zeta (14-3-3ζ), an important regulatory protein of YAP, may prevent the AKI-CKD transition. We established an AKI-CKD model in mice by unilateral renal ischemia-reperfusion injury and overexpressed 14-3-3ζ in mice using a fluid dynamics-based gene transfection technique. We also overexpressed and knocked down 14-3-3ζ in vitro. In AKI-CKD model mice, 14-3-3ζ expression was significantly increased at the AKI stage. During the development of chronic disease, the expression of 14-3-3ζ tended to decrease, whereas active YAP was consistently overexpressed. In vitro, we found that 14-3-3ζ can combine with YAP, promote the phosphorylation of YAP, inhibit YAP nuclear translocation, and reduce the expression of fibrosis-related proteins. In an in vivo intervention experiment, we found that the overexpression of 14-3-3ζ slowed the process of renal fibrosis in a mouse model of AKI-CKD. These findings suggest that 14-3-3ζ can affect the expression of fibrosis-related proteins by regulating YAP, inhibit the maladaptive repair of renal tubular epithelial cells, and prevent the AKI-CKD transition.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Molitoris BA. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest. 2014;124:2355–63.
Al-Jaghbeer M, Dealmeida D, Bilderback A, Ambrosino R, Kellum JA. Clinical decision support for in-hospital AKI. J Am Soc Nephrol. 2018;29:654–60.
Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41:1411–23.
Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81:442–8.
Hsu CY. Yes, AKI truly leads to CKD. J Am Soc Nephrol. 2012;23:967–9.
James MT, Bhatt M, Pannu N, Tonelli M. Long-term outcomes of acute kidney injury and strategies for improved care. Nat Rev Nephrol. 2020;16:193–205.
Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK. Failed Tubule Recovery, AKI-CKD transition, and kidney disease progression. J Am Soc Nephrol. 2015;26:1765–76.
Zhao L, Han F, Wang J, Chen J. Current understanding of the administration of mesenchymal stem cells in acute kidney injury to chronic kidney disease transition: a review with a focus on preclinical models. Stem Cell Res Ther. 2019;10:385.
Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med. 2010;16:535–43.
Chen J, You H, Li Y, Xu Y, He Q, Harris RC. EGF receptor-dependent YAP activation is important for renal recovery from AKI. J Am Soc Nephrol. 2018;29:2372–85.
Rausch V, Hansen CG. The Hippo Pathway, YAP/TAZ, and the plasma membrane. Trends Cell Biol. 2020;30:32–48.
Zhu C, Tabas I, Schwabe RF, Pajvani UB. Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis. Nat Rev Gastroenterol Hepatol. 2021;18:131–42.
Zhang T, He X, Caldwell L, Goru SK, Ulloa Severino L, Tolosa MF, et al. NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling. Sci Transl Med. 2022;14:eaaz4028.
Anorga S, Overstreet JM, Falke LL, Tang J, Goldschmeding RG, Higgins PJ, et al. Deregulation of Hippo-TAZ pathway during renal injury confers a fibrotic maladaptive phenotype. FASEB J. 2018;32:2644–57.
He X, Tolosa MF, Zhang T, Goru SK, Ulloa Severino L, Misra PS, et al. Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis. JCI Insight. 2022;7:e146243.
Liang M, Yu M, Xia R, Song K, Wang J, Luo J, et al. Yap/Taz deletion in Gli(+) cell-derived myofibroblasts attenuates fibrosis. J Am Soc Nephrol. 2017;28:3278–90.
Chen J, Wang X, He Q, Bulus N, Fogo AB, Zhang MZ, et al. YAP activation in renal proximal tubule cells drives diabetic renal interstitial fibrogenesis. Diabetes. 2020;69:2446–57.
Zhang B, Shi Y, Gong A, Pan Z, Shi H, Yang H, et al. HucMSC exosome-delivered 14-3-3zeta orchestrates self-control of the wnt response via modulation of YAP during cutaneous regeneration. Stem Cells. 2016;34:2485–500.
Zhu H, Liao J, Zhou X, Hong X, Song D, Hou FF, et al. Tenascin-C promotes acute kidney injury to chronic kidney disease progression by impairing tubular integrity via αvβ6 integrin signaling. Kidney Int. 2020;97:1017–31.
Skrypnyk NI, Harris RC, de Caestecker MP. Ischemia-reperfusion model of acute kidney injury and post injury fibrosis in mice. J Vis Exp. 2013:50495. https://doi.org/10.3791/50495.
Zhou D, Li Y, Zhou L, Tan RJ, Xiao L, Liang M, et al. Sonic hedgehog is a novel tubule-derived growth factor for interstitial fibroblasts after kidney injury. J Am Soc Nephrol. 2014;25:2187–200.
Liu F, Song Y, Liu D. Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther. 1999;6:1258–66.
Tajima T, Yoshifuji A, Matsui A, Itoh T, Uchiyama K, Kanda T, et al. beta-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects. Kidney Int. 2019;95:1120–37.
Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest. 2001;107:1145–52.
Brennan EP, Nolan KA, Börgeson E, Gough OS, McEvoy CM, Docherty NG, et al. Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1. J Am Soc Nephrol. 2013;24:627–37.
Thorenz A, Derlin K, Schroder C, Dressler L, Vijayan V, Pradhan P, et al. Enhanced activation of interleukin-10, heme oxygenase-1, and AKT in C5aR2-deficient mice is associated with protection from ischemia reperfusion injury-induced inflammation and fibrosis. Kidney Int. 2018;94:741–55.
Du T, Zhu YJ. The regulation of inflammatory mediators in acute kidney injury via exogenous mesenchymal stem cells. Mediators Inflamm. 2014;2014:261697.
Del Re DP, Yang Y, Nakano N, Cho J, Zhai P, Yamamoto T, et al. Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury. J Biol Chem. 2013;288:3977–88.
Londhe AD, Bergeron A, Curley SM, Zhang F, Rivera KD, Kannan A, et al. Regulation of PTP1B activation through disruption of redox-complex formation. Nat Chem Biol. 2020;16:122–5.
Reinhardt HC, Yaffe MB. Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat Rev Mol Cell Biol. 2013;14:563–80.
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 1996;87:619–28.
Yaffe MB, Rittinger K, Volinia S, Caron PR, Aitken A, Leffers H, et al. The structural basis for 14-3-3:phosphopeptide binding specificity. Cell. 1997;91:961–71.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68.
Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D, Frangioni JV, et al. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol. 2002;156:817–28.
Medina A, Ghahary A. Transdifferentiated circulating monocytes release exosomes containing 14-3-3 proteins with matrix metalloproteinase-1 stimulating effect for dermal fibroblasts. Wound Repair Regen. 2010;18:245–53.
Pozuelo-Rubio M. Regulation of autophagic activity by 14-3-3zeta proteins associated with class III phosphatidylinositol-3-kinase. Cell Death Differ. 2011;18:479–92.
Pozuelo-Rubio M. 14-3-3 proteins are regulators of autophagy. Cells. 2012;1:754–73.
Zannis-Hadjopoulos M, Yahyaoui W, Callejo M. 14-3-3 cruciform-binding proteins as regulators of eukaryotic DNA replication. Trends Biochem Sci. 2008;33:44–50.
Szeto SG, Narimatsu M, Lu M, He X, Sidiqi AM, Tolosa MF, et al. YAP/TAZ are mechanoregulators of TGF-β-Smad signaling and renal fibrogenesis. J Am Soc Nephrol. 2016;27:3117–28.
Iwakura T, Fujigaki Y, Fujikura T, Tsuji T, Ohashi N, Kato A, et al. Cytoresistance after acute kidney injury is limited to the recovery period of proximal tubule integrity and possibly involves Hippo-YAP signaling. Physiol Rep. 2017;5:e13310.
Xu J, Li PX, Wu J, Gao YJ, Yin MX, Lin Y, et al. Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector. Clin Sci. 2016;130:349–63.
Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008;28:2426–36.
Chen Q, Zhang N, Xie R, Wang W, Cai J, Choi KS, et al. Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. Genes Dev. 2015;29:1285–97.
Gewin L, Zent R. How does TGF-β mediate tubulointerstitial fibrosis? Semin Nephrol. 2012;32:228–35.
Kong JS, Park JH, Yoo SA, Kim KM, Bae YJ, Park YJ, et al. Dynamic transcriptome analysis unveils key proresolving factors of chronic inflammatory arthritis. J Clin Invest. 2020;130:3974–86.
Wang J, Jia H, Zhang B, Yin L, Mao F, Yu J, et al. HucMSC exosome-transported 14-3-3ζ prevents the injury of cisplatin to HK-2 cells by inducing autophagy in vitro. Cytotherapy. 2018;20:29–44.
Acknowledgements
This work was supported by the National Key R&D Program of China (2017YFA0103200, 2017YFA0103203) and the National Natural Science Foundation of China (No. 82030025, 81830060).
Author information
Authors and Affiliations
Contributions
XMC, LQW and LSZ designed the study; TTW, LLW, WJS, YHZ, JNL, BF, and XW carried out experiments; TTW drafted the paper; LLW, JW, LSZ, QGL and XYB revised the paper; all authors approved the final version of the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Wang, Tt., Wu, Ll., Wu, J. et al. 14-3-3ζ inhibits maladaptive repair in renal tubules by regulating YAP and reduces renal interstitial fibrosis. Acta Pharmacol Sin 44, 381–392 (2023). https://doi.org/10.1038/s41401-022-00946-y
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-022-00946-y
Keywords
This article is cited by
-
Estrogen receptor α suppresses hepatocellular carcinoma by restricting M2 macrophage infiltration through the YAP-CCL2 axis
BMC Cancer (2025)
-
Sirt1 Overexpression Inhibits Fibrous Scar Formation and Improves Functional Recovery After Cerebral Ischemic Injury Through the Deacetylation of 14–3-3ζ
Molecular Neurobiology (2023)
