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OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells

Acta Pharmacologica Sinica volume 45, pages 765–776 (2024)Cite this article

Abstract

Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 μg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 μM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.

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Fig. 1: OTUD1 deficiency alleviates Ang II-induced hypertensive renal injury.
Fig. 2: Otud1 deficiency alleviates Ang II-induced hypertensive renal injury.
Fig. 3: Overexpression of OTUD1 aggravates Ang II-induced hypertensive renal injury.
Fig. 4: OTUD1 regulates fibrotic and inflammatory responses in TCMK-1 cells.
Fig. 5: OTUD1 mediates Ang II-induced CDK9 activation.
Fig. 6: OTUD1 regulates the activity of CDK9 through deubiquitination.
Fig. 7: OTUD1 alleviates Ang II-induced hypertensive renal injury by regulating CDK9.

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References

  1. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan A, Lasserson DS, et al. Global prevalence of chronic kidney disease—a systematic review and meta-analysis. PLoS One. 2016;11:e0158765.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Rai A, Narisawa M, Li P, Piao LM, Li YL, Yang G, et al. Adaptive immune disorders in hypertension and heart failure: focusing on T-cell subset activation and clinical implications. J Hypertens. 2020;38:1878–89.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang J, Cao L, Wang XH, Li Q, Zhang M, Cheng C, et al. The E3 ubiquitin ligase TRIM31 plays a critical role in hypertensive nephropathy by promoting proteasomal degradation of MAP3K7 in the TGF-β1 signaling pathway. Cell Death Differ. 2022;29:556–67.

    Article  CAS  PubMed  Google Scholar 

  4. Zhou LL, Li YJ, Hao S, Zhou D, Tan RJ, Nie J, et al. Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling. J Am Soc Nephrol 2015;26:107–20.

    Article  CAS  PubMed  Google Scholar 

  5. Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol. 2006;17:1807–19.

    Article  CAS  PubMed  Google Scholar 

  6. Ihara Y, Morishima-Kawashima M, Nixon R. The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer’s disease. Cold Spring Harb Perspect Med. 2012;2:8.

    Article  Google Scholar 

  7. Roberts JZ, Crawford N, Longley DB. The role of ubiquitination in apoptosis and necroptosis. Cell Death Differ. 2022;29:272–84.

    Article  CAS  PubMed  Google Scholar 

  8. Cockram PE, Kist M, Prakash S, Chen SH, Wertz IE, Vucic D. Ubiquitination in the regulation of inflammatory cell death and cancer. Cell Death Differ. 2021;28:591–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oikawa D, Shimizu K, Tokunaga F. Pleiotropic roles of a KEAP1-associated deubiquitinase, OTUD1. Antioxidants. 2023;12:2.

    Article  Google Scholar 

  10. Song J, Liu TT, Yin Y, Zhao W, Lin ZQ, Yin YX, et al. The deubiquitinase OTUD1 enhances iron transport and potentiates host antitumor immunity. EMBO Rep. 2021;22:e51162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang MY, Han X, Yu TX, Wang MX, Luo W, Zou CP, et al. OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes. Theranostics. 2023;13:2263–80.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Huang ZQ, Shen SR, Wang MY, Li WX, Wu GJ, Huang WJ, et al. Mouse endothelial OTUD1 promotes angiotensin II-induced vascular remodeling by deubiquitinating SMAD3. EMBO Rep. 2023;24:e56135.

    Article  CAS  PubMed  Google Scholar 

  13. Guhan SM, Shaughnessy M, Rajadurai A, Taylor M, Kumar R, Ji ZY, et al. The molecular context of vulnerability for CDK9 suppression in triple wild-type melanoma. J Invest Dermatol. 2021;141:2018–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Olson CM, Jiang BS, Erb MA, Liang YK, Doctor ZM, Zhang ZN, et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat Chem Biol. 2018;14:163–70.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang ZM, Wang DD, Wang PY, Zhao YC, You FP. OTUD1 negatively regulates type I IFN induction by disrupting noncanonical ubiquitination of IRF3. J Immunol. 2020;204:1904–18.

    Article  CAS  PubMed  Google Scholar 

  16. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol Ther. 2008;16:1073–80.

    Article  CAS  PubMed  Google Scholar 

  17. Restrepo JM, Torres-Canchala L, Bonventre JV, Arias JC, Ferguson M, Villegas A, et al. Urinary KIM-1 is not correlated with gestational age among 5-year-old children born prematurely. Front Pediatr. 2023;11:1038206.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Karmakova ТА, Sergeeva NS, Kanukoev KY, Alekseev BY, Kaprin АD. Kidney injury molecule 1 (KIM-1): a multifunctional glycoprotein and biological marker (Review). Sovrem Tekhnologii Med. 2021;13:64–78.

    Article  PubMed  Google Scholar 

  19. Qu XL, Jiang MJ, Sun YB, Jiang XY, Fu P, Ren Y, et al. The Smad3/Smad4/CDK9 complex promotes renal fibrosis in mice with unilateral ureteral obstruction. Kidney Int. 2015;88:1323–35.

    Article  CAS  PubMed  Google Scholar 

  20. Yang XJ, Luo W, Li L, Hu X, Xu MJ, Wang Y, et al. CDK9 inhibition improves diabetic nephropathy by reducing inflammation in the kidneys. Toxicol Appl Pharmacol 2021;416:115465.

    Article  CAS  PubMed  Google Scholar 

  21. Thrower JS, Hoffman L, Rechsteiner M, Pickart CM. Recognition of the polyubiquitin proteolytic signal. EMBO J. 2000;19:94–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mukhopadhyay D, Riezman H. Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science. 2007;315:201–5.

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123:773–86.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang Y, Hu RM, Wu HJ, Jiang WN, Sun Y, Wang Y, et al. OTUB1 overexpression in mesangial cells is a novel regulator in the pathogenesis of glomerulonephritis through the decrease of DCN level. PLoS One. 2012;7:e29654.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. Park JH, Kim SY, Cho HJ, Lee SY, Baek KH. YOD1 Deubiquitinates NEDD4 involved in the Hippo signaling pathway. Cell Physiol Biochem. 2020;54:1–14.

    CAS  PubMed  Google Scholar 

  26. Zhao Y, Chen X, Lin YM, Li ZD, Su X, Fan SJ, et al. USP25 inhibits renal fibrosis by regulating TGFβ-SMAD signaling pathway in Ang II-induced hypertensive mice. Biochim Biophys Acta Mol Basis Dis. 2023;1869:166713.

    Article  CAS  PubMed  Google Scholar 

  27. Liu WT, Yan B, Yu HX, Ren JN, Peng M, Zhu L, et al. OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs. Int J Biol Sci. 2022;18:1401–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vdovin A, Jelinek T, Zihala D, Sevcikova T, Durech M, Sahinbegovic H, et al. The deubiquitinase OTUD1 regulates immunoglobulin production and proteasome inhibitor sensitivity in multiple myeloma. Nat Commun. 2022;13:6820.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huang Z, Wang TQ, Wang C, Fan Y. CDK9 inhibitors in cancer research. RSC Med Chem. 2022;13:688–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kudin AP, Bimpong-Buta NY, Vielhaber S, Elger CE, Kunz WS. Characterization of superoxide-producing sites in isolated brain mitochondria. J Biol Chem. 2004;279:4127–35.

    Article  CAS  PubMed  Google Scholar 

  31. Russo AA, Jeffrey PD, Pavletich NP. Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat Struct Biol. 1996;3:696–700.

    Article  CAS  PubMed  Google Scholar 

  32. Ramakrishnan R, Dow EC, Rice AP. Characterization of Cdk9 T-loop phosphorylation in resting and activated CD4+ T lymphocytes. J Leukoc Biol. 2009;86:1345–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fu JJ, Yoon HG, Qin J, Wong JM. Regulation of P-TEFb elongation complex activity by CDK9 acetylation. Mol Cell Biol. 2007;27:4641–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mbonye U, Wang BL, Gokulrangan G, Shi WX, Yang SC, Karn J. Cyclin-dependent kinase 7 (CDK7)-mediated phosphorylation of the CDK9 activation loop promotes P-TEFb assembly with Tat and proviral HIV reactivation. J Biol Chem. 2018;293:10009–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Oikawa D, Gi M, Kosako H, Shimizu K, Takahashi H, Shiota M, et al. OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways. Cell Death Dis. 2022;13:694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu B, Qiang LH, Zhang Y, Fu YS, Zhao MY, Lei ZH, et al. The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling. Cell Mol Immunol. 2022;19:276–89.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (82000793 to WL and 82370829 for HZ) and the Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A) at Hangzhou Medical College.

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Author notes

  1. These authors contributed equally: Meng-yang Wang, Tian-xiang Yu

Authors and Affiliations

  1. Department of Pharmacy and Institute of Inflammation, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, 310014, China

    Meng-yang Wang, Tian-xiang Yu, Qin-yan Wang, Xue Han & Guang Liang

  2. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Meng-yang Wang, Tian-xiang Yu, Qin-yan Wang, Xue Han, Shi-ju Ye, Xiao-hong Long, Yi Wang, Wu Luo & Guang Liang

  3. Department of Pharmacology, College of Pharmacy, Beihua University, Jilin, 132013, China

    Meng-yang Wang

  4. Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China

    Xiang Hu & Hong Zhu

  5. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310014, China

    Guang Liang

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Contributions

GL, HZ, and WL contributed to the literature search and study design. MYW, TXY, QYW, XH, SJY, and XH carried out the experiments. WL and MYW contributed to data collection and analysis. MYW and WL participated in the drafting of the article. GL, YW, and XHL revised the manuscript.

Corresponding authors

Correspondence to Wu Luo or Guang Liang.

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Wang, My., Yu, Tx., Wang, Qy. et al. OTUD1 promotes hypertensive kidney fibrosis and injury by deubiquitinating CDK9 in renal epithelial cells. Acta Pharmacol Sin 45, 765–776 (2024). https://doi.org/10.1038/s41401-023-01192-6

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