*Purpose: Pyroptosis, a pro-inflammatory form of cell death, is dependent on membrane pore formation through the assembly of cleaved Gasdermin-D molecules. We hypothesized that this is important in the pathophysiology of ischemia-reperfusion injury (IRI).

*Methods: Male C57BL/6 mice were exposed to ethyl-N-nitrosourea mutagenesis, leading to an isoleucine to asparagine mutation (I105N) in the GasderminD gene. Chimeric mice were generated by whole body irradiation, followed by infusion of syngeneic donor bone marrow cells. Age- and gender-matched littermate control wild-type, heterozygous and homozygous GasderminD^I105N mice and chimeric mice were subjected to bilateral renal IRI (36°C, 22mins). Mice were analyzed 24-hours post-reperfusion for renal function, histology and biomolecular phenotyping.

*Results: Homozygote and heterozygote GasderminD^I105N mice were protected from renal IRI in a gene dose-dependent manner when compared to wild-type, demonstrating lower mean serum creatinine (15.7, 48.1 and 85.5µmol/L respectively, p<0.001), less histological tubular injury and cell death (1.8, 3.6 and 5.1 TUNEL+ cells/hpf, p<0.01) and decreased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, RANTES). Chimer mice were checked for engraftment after 8 weeks. The susceptibility of GasderminD^I105N chimeric mice (receiving wild-type donor bone marrow) to IRI was similar to that of wild-type controls, indicating that hematopoietic cells rather than parenchymal cells, are key drivers of injury.

*Conclusions: GasderminD^I105N mice were protected from IRI and demonstrates the importance of the pyroptosis pathway on acute kidney injury. Manipulation of GasderminD is an attractive target to mitigate inflammation and cellular death following injury.

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