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Abstract: FR-OR08

Gasdermin D-Deficient Mice Are Hypersensitive to Necroptosis-Mediated AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tonnus, Wulf, Technische Universitat Dresden, Dresden, Sachsen, Germany
  • Belavgeni, Alexia, Technische Universitat Dresden, Dresden, Sachsen, Germany
  • Maremonti, Francesca, Technische Universitat Dresden, Dresden, Sachsen, Germany
  • von Mässenhausen, Anne, Technische Universitat Dresden, Dresden, Sachsen, Germany
  • Becker, Jan U., Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany
  • Hugo, Christian, Technische Universitat Dresden, Dresden, Sachsen, Germany
  • Linkermann, Andreas, Technische Universitat Dresden, Dresden, Sachsen, Germany

Group or Team Name

  • AG Linkermann
Background

Within the last decade, a central role for regulated necrosis (RN) in the pathophysiology of renal ischemia/reperfusion injury (IRI) has been established. RN is an umbrella term for several RN subtypes. With respect to the kidney, necroptosis and ferroptosis are the best studied pathways. However, the role of pyroptosis, a highly inflammatory RN type dependent on the protein GSDMD (gasdermin D), during IRI remains unclear.

Methods

Acute kidney injury was induced by IRI or cisplatin application in wild type and GSDMD-ko mice. Furthermore, GSDMD/GSDME-dko mice were utilized in these models to broaden the biological understandings. Mechanistically, MLKL/GSDMD-dko mice (deficient for both necroptosis and pyroptosis) were generated and tested as l. Additionally, immunohistochemistry in murine and human kidney samples as well as experimental work in freshly isolated murine kidney tubules and cell culture were performed.

Results

We investigated gasdermin D- and gasdermin E-deficient mice in a well-established model of moderate IRI. Both strains showed more severe AKI than matched wildtypes as demonstrated by higher levels of serum creatinine and urea as well as more severe tubular damage. This effect was neither dependent on increased tubular cell death as measured by LDH release from freshly isolated murine tubules nor on increased infiltration by CD3+ or CD68+ cells. Based on previous studies, we speculated that pyroptosis-deficiency might promote necroptosis during AKI. To test this hypothesis, we generated MLKL/GSDMD-dko. In IRI, co-deletion of MLKL ameliorated the effects of pyroptosis-deficiency and led to reduced levels of serum creatinine and urea as well as reduced tubular damage compared to both wildtype and pyroptosis-deficient mice. Furthermore, we investigated whether this interaction of pyroptosis and necroptosis is transferable to other forms of AKI by utilizing cisplatin-induced tubular injury as a second model. Again, pyroptosis-deficient mice were more sensitive to AKI and could be protected by co-deletion of MLKL.

Conclusion

In summary, Gasdermin D and E appear to have protective roles in murine AKI as they help to reduce MLKL-mediated necroptosis. Our data are in striking contrast to previously published data (Miao et al., Kidney International 2019).

Funding

  • Private Foundation Support