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Inhibition of Ubiquitin-specific Protease 4 Attenuates Epithelial—Mesenchymal Transition of Renal Tubular Epithelial Cells via Transforming Growth Factor Beta Receptor Type I

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Abstract

Objective

Ubiquitin-specific protease 4 (USP4) facilitates the development of transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in various cancer cells. Moreover, EMT of renal tubular epithelial cells (RTECs) is required for the progression of renal interstitial fibrosis. However, the role of USP4 in EMT of RTECs remains unknown. The present study aimed to explore the effect of USP4 on the EMT of RTECs as well as the involved mechanism.

Methods

In established unilateral ureteral obstruction (UUO) rats and NRK-52E cells, immunohistochemistry and Western blot assays were performed.

Results

USP4 expression was increased significantly with obstruction time. In NRK-52E cells stimulated by TGF-β1, USP4 expression was increased in a time-dependent manner. In addition, USP4 silencing with specific siRNA indicated that USP4 protein was suppressed effectively. Meanwhile, USP4 siRNA treatment restored E-cadherin and weakened alpha smooth muscle actin (α-SMA) expression, indicating that USP4 may promote EMT. After treatment with USP4 siRNA and TGF-β1 for 24 h, the expression of TGF-β1 receptor type I (TβRI) was decreased.

Conclusion

USP4 promotes the EMT of RTECs through upregulating TβRI, thereby facilitating renal interstitial fibrosis. These findings may provide a potential target of USP4 in the treatment of renal fibrosis.

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References

  1. Panizo S, Martínez-Arias L, Alonso-Montes C, et al. Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences. Int J Mol Sci, 2021,22(1):408

    Article  CAS  PubMed Central  Google Scholar 

  2. Liu BC, Tang TT, Lv LL. How Tubular Epithelial Cell Injury Contributes to Renal Fibrosis. Adv Exp Med Biol, 2019,1165:233–252

    Article  CAS  PubMed  Google Scholar 

  3. Humphreys BD. Mechanisms of Renal Fibrosis. Annu Rev Physiol, 2018,80:309–326

    Article  CAS  PubMed  Google Scholar 

  4. Sheng LL, Zhuang SG. New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis. Front Physiol, 2020,11:569322

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yuan Q, Tan RJ, Liu Y. Myofibroblast in Kidney Fibrosis: Origin, Activation, and Regulation. Adv Exp Med Biol, 2019,1165:253–283

    Article  CAS  PubMed  Google Scholar 

  6. Ruiz-Ortega M, Rayego-Mateos S, Lamas S, et al. Targeting the progression of chronic kidney disease. Nat Rev Nephrol, 2020;16(5):269–288

    Article  PubMed  Google Scholar 

  7. Faktor J, Pjechová M, Hernychová L, et al. Protein Ubiquitination Research in Oncology. Klin Onkol, 2019,32:56–64

    Article  CAS  PubMed  Google Scholar 

  8. Song L, Luo ZQ. Post-translational regulation of ubiquitin signaling. J Cell Biol, 2019,218(6):1776–1786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li O, Ma Q, Li F, et al. Progress of small ubiquitin-related modifiers in kidney diseases. Chin Med J (Engl), 2019,132(4):466–473

    Article  CAS  Google Scholar 

  10. Meyer-Schwesinger C. The ubiquitin-proteasome system in kidney physiology and disease. Nat Rev Nephrol, 2019,15(7):393–411

    Article  PubMed  Google Scholar 

  11. Young MJ, Hsu KC, Lin TE, et al. The role of ubiquitin-specific peptidases in cancer progression. J Biomed Sci, 2019,26(1):42

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lai KP, Chen J, Tse WKF. Role of Deubiquitinases in Human Cancers: Potential Targeted Therapy. Int J Mol Sci, 2020,21(7):2548

    Article  CAS  PubMed Central  Google Scholar 

  13. Hu B, Zhang D, Zhao K, et al. Spotlight on USP4: Structure, Function, and Regulation. Front Cell Dev Biol, 2021,9:595159

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang Y, Zhou L, Lu J, et al. USP4 function and multifaceted roles in cancer: a possible and potential therapeutic target. Cancer Cell Int, 2020,20:298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Martínez-Klimova E, Aparicio-Trejo OE, Tapia E, et al. Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments. Biomolecules, 2019, 9(4):141

    Article  PubMed Central  Google Scholar 

  16. Lovisa S, Zeisberg M, Kalluri R. Partial Epithelial-to-Mesenchymal Transition and Other New Mechanisms of Kidney Fibrosis. Trends Endocrinol Metab, 2016,27(10):681–695

    Article  CAS  PubMed  Google Scholar 

  17. Pu JY, Zhang Y, Zhou JH. Effect of Huai Qi Huang on Epithelial-Mesenchymal Transition of Renal Tubular Epithelial Cells through miR-200a. Evid Based Complement Alternat Med, 2016,2016:8612190

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu BC, Tang TT, Lv LL, et al. Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int, 2018,93(3):568–579

    Article  CAS  PubMed  Google Scholar 

  19. Zhang L, Chen Q, Chen Z, et al. Mechanisms Regulating Muscle Protein Synthesis in CKD. J Am Soc Nephrol, 2020,31(11):2573–2587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gai Z, Zhou G, Gui T, et al. Trps1 haploinsufficiency promotes renal fibrosis by increasing Arkadia expression. J Am Soc Nephrol, 2010,21(9):1468–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen L, Yang T, Lu DW, et al. Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment. Biomed Pharmacother, 2018,101:670–681

    Article  CAS  PubMed  Google Scholar 

  22. Cui TG, Ichikawa T, Yang M, et al. An emerging role of deubiquitinating enzyme cylindromatosis (CYLD) in the tubulointerstitial inflammation of IgA nephropathy. Biochem Biophys Res Commun, 2009,390(2):307–312

    Article  CAS  PubMed  Google Scholar 

  23. Huang K, Zhao X. USP9X prevents AGEs-induced upregulation of FN and TGF-β1 through activating Nrf2-ARE pathway in rat glomerular mesangial cells. Exp Cell Res, 2020,393(2):112100

    Article  CAS  PubMed  Google Scholar 

  24. Soji K, Doi S, Nakashima A, et al. Deubiquitinase inhibitor PR-619 reduces Smad4 expression and suppresses renal fibrosis in mice with unilateral ureteral obstruction. PloS One, 2018,13(8):e0202409

    Article  PubMed  PubMed Central  Google Scholar 

  25. He B, Zhao YC, Gao LC, et al. Ubiquitin-Specific protease 4 is an endogenous negative regulator of pathological cardiac hypertrophy. Hypertension, 2016, 67(6):1237–1248

    Article  CAS  PubMed  Google Scholar 

  26. Xu J, Chen D, Jin L, et al. Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling. J Cell Mol Med, 2021,25(2):1140–1150

    Article  CAS  PubMed  Google Scholar 

  27. Zhang J, Na S, Pan S, et al. Inhibition of USP4 attenuates pathological scarring by downregulation of the TGF-β/Smad signaling pathway. Mol Med Rep, 2019,20(2):1429–1435

    CAS  PubMed  Google Scholar 

  28. Li F, Hu Q, He T, et al. The Deubiquitinase USP4 stabilizes Twist1 protein to promote lung cancer cell stemness. Cancers (Basel), 2020,12(6):1582

    Article  CAS  Google Scholar 

  29. Qiu C, Liu Y, Mei Y, et al. Ubiquitin-specific protease 4 promotes metastasis of hepatocellular carcinoma by increasing TGF-β signaling-induced epithelial-mesenchymal transition. Aging (Albany NY), 2018, 10(10):2783–2799

    Article  CAS  Google Scholar 

  30. Xiao L, Peng X, Liu F, et al. AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by Smurf2 and deubiquitinating enzyme USP4. BMC Cell Biol, 2015,16:7

    Article  PubMed  PubMed Central  Google Scholar 

  31. Qin N, Han F, Li L, et al. Deubiquitinating enzyme 4 facilitates chemoresistance in glioblastoma by inhibiting P53 activity. Oncol Lett, 2019,17(1):958–964

    CAS  PubMed  Google Scholar 

  32. Zhou Y, Liang P, Ji W, et al. Ubiquitin-specific protease 4 promotes glioblastoma multiforme via activating ERK pathway. Onco Targets Ther, 2019,12:1825–1839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li T, Yan B, Ma Y, et al. Ubiquitin-specific protease 4 promotes hepatocellular carcinoma progression via cyclophilin A stabilization and deubiquitination. Cell Death Dis, 2018,9(2):148

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ma TT, Meng XM. TGF-β/Smad and Renal Fibrosis. Adv Exp Med Biol, 2019,1165:347–364

    Article  CAS  PubMed  Google Scholar 

  35. Gu YY, Liu XS, Huang XR, et al. Diverse role of TGF-β in kidney disease. Front Cell Dev Biol, 2020,8:123

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ahmadi A, Najafi M, Farhood B, et al. Transforming growth factor-β signaling: Tumorigenesis and targeting for cancer therapy. J Cell Physiol, 2019,234(8):12173–12187

    Article  CAS  PubMed  Google Scholar 

  37. Vander Ark A, Cao J, Li X. TGF-β receptors: In and beyond TGF-β signaling. Cell Signal, 2018,52:112–120

    Article  CAS  PubMed  Google Scholar 

  38. Kim SY, Baek KH. TGF-β signaling pathway mediated by deubiquitinating enzymes. Cell Mol Life Sci, 2019,76(4):653–665

    Article  CAS  PubMed  Google Scholar 

  39. Vlasschaert C, Xia X, Coulombe J, et al. Evolution of the highly networked deubiquitinating enzymes USP4, USP15, and USP11. BMC Evol Biol, 2015,15:230

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zhang L, Zhou F, Drabsch Y, et al. USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor. Nat Cell Biol, 2012,14(7):717–726

    Article  CAS  PubMed  Google Scholar 

  41. Liao W, Liang P, Liu B, et al. MicroRNA-140-5p mediates renal fibrosis through TGF-β1/Smad signaling pathway by directly targeting TGFBR1. Front Physiol, 2020,11:1093

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jin-yun Pu, Yu Zhang, Li-xia Wang, Jie Wang & Jian-hua Zhou

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  1. Jin-yun Pu
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  2. Yu Zhang
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  3. Li-xia Wang
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  4. Jie Wang
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  5. Jian-hua Zhou
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Correspondence to Jian-hua Zhou.

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Pu, Jy., Zhang, Y., Wang, Lx. et al. Inhibition of Ubiquitin-specific Protease 4 Attenuates Epithelial—Mesenchymal Transition of Renal Tubular Epithelial Cells via Transforming Growth Factor Beta Receptor Type I. CURR MED SCI 42, 1000–1006 (2022). https://doi.org/10.1007/s11596-022-2632-2

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  • DOI: https://doi.org/10.1007/s11596-022-2632-2

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