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Kidney Week

Abstract: TH-PO044

Insights into the Pathophysiological Role of Gasdermin D: Assessment of Murine AKI and Human Biopsies

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tonnus, Wulf, Technische Universität Dresden, Dresden, Germany
  • Linkermann, Andreas, University Hospital Carl Gustav Carus Dresden, Dresden, Germany

Group or Team Name

  • AG Linkermann
Background

Regulated cell death (RCD) has been used synonymously to apoptosis for years; however, within the last decade it was discovered that necrotic cell death can be regulated as well. Some forms of RCD, namely necroptosis and ferroptosis, have been found to be critically involved in the pathogenesis of acute kidney injury (AKI) in vivo. Pyroptosis is another form of regulated necrosis, which depends on cleavage of Gasdermin D by inflammatory caspases, such as CASP-1 and CASP11. After cleavage, Gasdermin D N-terminal domains assemble and form pores in the cell membrane. As pyroptosis is highly immunogenic, we aimed to evaluate whether pyroptosis is involved in the pathogenesis of AKI.

Methods

We evaluated GSDMD-deficient mice in two commonly-used models of AKI: Ischemia-Reperfusion-injury (IRI) and Cisplatin-induced AKI.
Additionally, we generated mice deficient for both necroptosis and pyroptosis (GSDMD-MLKL-dko mice) to test them in the same models.
Furthermore, we stained human kidney biopsy samples immunohistochemically for cleaved GSDMD.

Results

We found GSDMD-deficient mice to be sensitive when AKI was induced by the chemotherapeutic agent cisplatin as assessed by serum markers of AKI (creatinin and urea) and histological damage 24h and 48h after cisplatin injection. In renal ischemia-reperfusion injury (IRI), and in contrast to the protective effects of necroptosis-deficiency or pharmacological ferroptosis inhibition, GSDMD-deficient mice were not protected in this model, but rather demonstrated slightly deteriorated functional values.
Also, we evaluated our freshly-generated GSDMD-MLKL-dko mice in the above-mentioned models. The results have not been entirely read out by the time of abstract submission.
Finally, we detected cleaved GSDMD in human biopsy samples; thus, demonstrating involvement of pyroptosis in human AKI for the first time.

Conclusion

In conclusion, the role played by Gasdermin D in AKI is unexpected: whereas inhibition of other forms of regualted necrosis is known to be beneficial, inhibition of pyroptosis increased kidney damage. This raises questions regarding the complex interplay between different forms of regulated necrosis in AKI.

Funding

  • Government Support - Non-U.S.