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GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy


Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.

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Fig. 1: UUO- induced Casp3/GSDME activation and renal tubular cell necrosis increased in the kidney.
Fig. 2: Gsdme deficiency alleviated renal tubular damage, hydronephrosis, and fibrogenesis in the UUO model.
Fig. 3: Bone marrow-derived cells with Gsdme deficiency did not reduce renal tubular damage and renal fibrosis progression after UUO.
Fig. 4: Real tubular damage and fibrogenesis were reduced in UUO mice with specific deletion of Casp3 in renal tubules, but not in hematopoietic cells.
Fig. 5: Gsdme and Casp3 deficiency improved renal function and inhibited fibrosis progression in the kidney with reversible unilateral ureteral obstruction (R-UUO).
Fig. 6: Gsdme−/−, Casp3−/− and Ksp-cre Casp3fl/fl mice displayed a reduction of renal tubulointerstitial inflammation post-UUO.
Fig. 7: Specific deletion Hmgb1 in renal tubular cells reduced fibrosis progression and inflammatory cells infiltration in the R-UUO model.
Fig. 8: Caspase3 cleaved GSDME in over-expressing GSDME of renal tubular cells (RTCs) in vitro to induce cell death and release HMGB1.


  1. 1.

    Stevens S. Obstructive kidney disease. Nurs Clin North Am. 2018;53:569–78.

    PubMed  Google Scholar 

  2. 2.

    Capelouto CC, Saltzman B. The pathophysiology of ureteral obstruction. J Endourol. 1993;7:93–103.

    CAS  PubMed  Google Scholar 

  3. 3.

    Park HC, Yasuda K, Ratliff B, Stoessel A, Sharkovska Y, Yamamoto I, et al. Postobstructive regeneration of kidney is derailed when surge in renal stem cells during course of unilateral ureteral obstruction is halted. Am J Physiol Ren Physiol. 2010;298:F357–364.

    CAS  Google Scholar 

  4. 4.

    Cochrane AL, Kett MM, Samuel CS, Campanale NV, Anderson WP, Hume DA, et al. Renal structural and functional repair in a mouse model of reversal of ureteral obstruction. J Am Soc Nephrol. 2005;16:3623–30.

    CAS  PubMed  Google Scholar 

  5. 5.

    Vilaysane A, Chun J, Seamone ME, Wang W, Chin R, Hirota S, et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J Am Soc Nephrol. 2010;21:1732–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Xiao X, Du C, Yan Z, Shi Y, Duan H, Ren Y. Inhibition of necroptosis attenuates kidney inflammation and interstitial fibrosis induced by unilateral ureteral obstruction. Am J Nephrol. 2017;46:131–8.

    CAS  PubMed  Google Scholar 

  7. 7.

    Yang B, Lan S, Dieudé M, Sabo-Vatasescu J-P, Karakeussian-Rimbaud A, Turgeon J, et al. Caspase-3 is a pivotal regulator of microvascular rarefaction and renal fibrosis after ischemia-reperfusion injury. J Am Soc Nephrol. 2018;29:1900–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Imamura M, Moon J-S, Chung K-P, Nakahira K, Muthukumar T, Shingarev R, et al. RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase. JCI Insight. 2018;3:e94979.

    PubMed Central  Google Scholar 

  9. 9.

    Chevalier RL, Forbes MS, Thornhill BA. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int. 2009;75:1145–52.

    PubMed  Google Scholar 

  10. 10.

    Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Ren Physiol. 2002;283:F861–875.

    Google Scholar 

  11. 11.

    Mack M. Inflammation and fibrosis. Matrix Biol. 2018;68–69:106–21.

    PubMed  Google Scholar 

  12. 12.

    Marchal P-O, Kavvadas P, Abed A, Kazazian C, Authier F, Koseki H, et al. Reduced NOV/CCN3 Expression limits inflammation and interstitial renal fibrosis after obstructive nephropathy in mice. PLoS ONE. 2015;10:e0137876.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Xu J, Jiang Y, Wang J, Shi X, Liu Q, Liu Z, et al. Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis. Cell Death Differ. 2014;21:1229–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2019;26:99–114.

    PubMed  Google Scholar 

  15. 15.

    Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol. 2015;11:264–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Chen H, Fang Y, Wu J, Chen H, Zou Z, Zhang X, et al. RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD. Cell Death Dis. 2018;9:878.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Xu Y, Ma H, Shao J, Wu J, Zhou L, Zhang Z, et al. A role for tubular necroptosis in cisplatin-induced AKI. J Am Soc Nephrol. 2015;26:2647–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Tonnus W, Belavgeni A, Xu Y, Linkermann A. Don’t trick me twice! Kidney Int. 2019;95:736–8.

    PubMed  Google Scholar 

  19. 19.

    Xu Y, Han J. The necrosome in acute kidney injury. Semin Nephrol. 2016;36:199–207.

    CAS  PubMed  Google Scholar 

  20. 20.

    Mulay SR, Honarpisheh MM, Foresto-Neto O, Shi C, Desai J, Zhao ZB, et al. Mitochondria permeability transition versus necroptosis in oxalate-induced AKI. J Am Soc Nephrol. 2019;30:1857–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 2016;535:111–6.

    CAS  PubMed  Google Scholar 

  22. 22.

    Orning P, Lien E, Fitzgerald KA. Gasdermins and their role in immunity and inflammation. J Exp Med. 2019;216:2453–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Broz P, Pelegrín P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20:143–57.

    CAS  PubMed  Google Scholar 

  24. 24.

    Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.

    CAS  PubMed  Google Scholar 

  25. 25.

    Wang K, Sun Q, Zhong X, Zeng M, Zeng H, Shi X, et al. Structural mechanism for GSDMD targeting by autoprocessed caspases in pyroptosis. Cell. 2020;180:941–955.e20.

    CAS  PubMed  Google Scholar 

  26. 26.

    Wang Y, Gao W, Shi X, Ding J, Liu W, He H, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547:99–103.

    CAS  PubMed  Google Scholar 

  27. 27.

    Zhang Z, Zhang Y, Xia S, Kong Q, Li S, Liu X, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020;579:415–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Yang X, Cheng X, Tang Y, Qiu X, Wang Y, Kang H, et al. Bacterial endotoxin activates the coagulation cascade through gasdermin D-dependent phosphatidylserine exposure. Immunity. 2019;51:983–996.e6.

    CAS  PubMed  Google Scholar 

  29. 29.

    Chen H, Li Y, Wu J, Li G, Tao X, Lai K, et al. RIPK3 collaborates with GSDMD to drive tissue injury in lethal polymicrobial sepsis. Cell Death Differ. 2020;27:2568–85.

    CAS  PubMed  Google Scholar 

  30. 30.

    Julien O, Wells JA. Caspases and their substrates. Cell Death Differ. 2017;24:1380–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Shao X, Somlo S, Igarashi P. Epithelial-specific Cre/lox recombination in the developing kidney and genitourinary tract. J Am Soc Nephrol. 2002;13:1837–46.

    CAS  PubMed  Google Scholar 

  32. 32.

    Yanai H, Ban T, Wang Z, Choi MK, Kawamura T, Negishi H, et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature. 2009;462:99–103.

    CAS  PubMed  Google Scholar 

  33. 33.

    Buchtler S, Grill A, Hofmarksrichter S, Stöckert P, Schiechl-Brachner G, Rodriguez Gomez M, et al. Cellular origin and functional relevance of collagen I production in the kidney. J Am Soc Nephrol. 2018;29:1859–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    de Boer J, Williams A, Skavdis G, Harker N, Coles M, Tolaini M, et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur J Immunol. 2003;33:314–25.

    PubMed  Google Scholar 

  35. 35.

    Cai J, Yuan H, Wang Q, Yang H, Al-Abed Y, Hua Z, et al. HMGB1-driven inflammation and intimal hyperplasia after arterial injury involves cell-specific actions mediated by TLR4. Arterioscler Thromb Vasc Biol. 2015;35:2579–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Pill J, Kraenzlin B, Jander J, Sattelkau T, Sadick M, Kloetzer H-M, et al. Fluorescein-labeled sinistrin as marker of glomerular filtration rate. Eur J Med Chem. 2005;40:1056–61.

    CAS  PubMed  Google Scholar 

  37. 37.

    Chen L, Kim SM, Oppermann M, Faulhaber-Walter R, Huang Y, Mizel D, et al. Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsalpha in juxtaglomerular cells. Am J Physiol Ren Physiol. 2007;292:F27–37.

    CAS  Google Scholar 

  38. 38.

    He W, Wan H, Hu L, Chen P, Wang X, Huang Z, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015;25:1285–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Rogers C, Erkes DA, Nardone A, Aplin AE, Fernandes-Alnemri T, Alnemri ES. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat Commun. 2019;10:1689.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. 2019;26:146–61.

    PubMed  Google Scholar 

  41. 41.

    Krajewski W, Wojciechowska J, Dembowski J, Zdrojowy R, Szydełko T. Hydronephrosis in the course of ureteropelvic junction obstruction: an underestimated problem? Current opinions on the pathogenesis, diagnosis and treatment. Adv Clin Exp Med. 2017;26:857–64.

    PubMed  Google Scholar 

  42. 42.

    Duffield JS. Cellular and molecular mechanisms in kidney fibrosis. J Clin Investig. 2014;124:2299–306.

    CAS  PubMed  Google Scholar 

  43. 43.

    Deng M, Tang Y, Li W, Wang X, Zhang R, Zhang X, et al. The endotoxin delivery protein HMGB1 mediates caspase-11-dependent lethality in sepsis. Immunity. 2018;49:740–753.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Hesketh EE, Vernon MA, Ding P, Clay S, Borthwick G, Conway B, et al. A murine model of irreversible and reversible unilateral ureteric obstruction. J Vis Exp. 2014;20:52559.

    Google Scholar 

  45. 45.

    Tian S, Li C, Ran R, Chen S-Y. Surfactant protein A deficiency exacerbates renal interstitial fibrosis following obstructive injury in mice. Biochim Biophys Acta Mol Basis Dis. 2017;1863:509–17.

    CAS  PubMed  Google Scholar 

  46. 46.

    Zhang C, Dong H, Chen F, Wang Y, Ma J, Wang G. The HMGB1-RAGE/TLR-TNF-α signaling pathway may contribute to kidney injury induced by hypoxia. Exp Ther Med. 2019;17:17–26.

    CAS  PubMed  Google Scholar 

  47. 47.

    Wyczanska M, Lange-Sperandio B. DAMPs in unilateral ureteral obstruction. Front Immunol. 2020;11:581300.

    CAS  PubMed  PubMed Central  Google Scholar 

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We are grateful to Pro. Feng Shao (Beijing National Institute of Biological Sciences) and Jiahuai Han (Xiamen University) for research information and experimental materials.

Funding statement

This work was supported by grants from National Natural Science Foundation of China (No. 82070720, No. 81870472 and No. 81700596), Joint Funds for the Innovation and Natural Science Foundation of Science and Technology of Fujian province (No. 2019Y9019 and No. 2020J02020), Fujian Province finance project (2020B009) and Startup Fund for Scientific Research of Fujian Medical University (No. 2019QH2037).

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YX, TWM, and HYL conceived and designed the research. YL, YY, ZXH, HC, KL, HBM, and ZC performed animal experiments. YL, YY, RL, ZW, ZC, and HBM performed all in vitro experiments. RL, HC, ZZ, and YX performed histologic analysis and flow cytometry. YL, KL, HC, ZZ, HYL, and YX analyzed the data. TWM and YX supervised the research. YL, YY, and YX wrote the original draft. TWM and YX performed writing-review and editing. All authors read and approved the final paper.

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Correspondence to Tak W. Mak or Yanfang Xu.

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The authors declare no competing interests.

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The manuscript reporting studies did not involve human participants, human data or human tissue. The animal experiments were accomplished in compliance with ethical standards. All the animal experiments were performed with the approval of the Laboratory Animal Management and Ethics Committee of Fujian Medical University, according to the Chinese Guidelines on the Care and Use of Laboratory Animals.

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Li, Y., Yuan, Y., Huang, Zx. et al. GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy. Cell Death Differ (2021).

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