Apoptosis contributes renal ischemia reperfusion (IR) injury and recovery to a greater degree in females compared to males

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Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication in hospital settings with high mortality rates. Patients who recover from AKI are at increased risk for chronic kidney disease (CKD), cardiovascular events and all-cause mortality. However, the mechanisms mediating these events not well understood. There are established sex differences in the susceptibility of cells to cell death, with cells from males having greater susceptibility to necrosis while cells from females are more likely to undergo apoptotic cell death in response to stress. Renal ischemia causes both apoptotic and necrotic cell death in the kidney. While the role of necrosis has been examined, the functional significance of apoptosis on renal recovery from IR in males and females has not been well studied. The goal of the current study was to test the hypothesis that renal apoptotic cell death contributes to renal IR injury to a greater extent in females than in males. 13-week-old male and female Sprague Dawley (SD) rats were subjected to sham or 50-minute warm bilateral IR (n=5/group). Additional male and females SD IR rats were then randomized to receive Z-VAD-FMK, a cell permeable pan-caspase inhibitor (1 mg/kg i.p.; n=5/group/every day) for 7-day post IR. Blood was collected from all rats 1 and 7 days after IR; kidneys were harvested 7 days post-IR for biochemical and histological analyses. Renal cell death was measured by TUNEL staining and flow cytometry. IR increased plasma creatinine (Pcr) in both male and female SD rat compared to respective sham controls at 24 hrs (P IR =0.0001; P sex*IR =0.92) and remain elevated at 7 days post-IR (P IR =0.0001; P sex*IR =0.07). Impaired kidney function was associated with greater apoptosis (P sex =0.001; P sex * IR =0.05) with caspase-3 activity (P sex =0.001; P sex * IR =0.007) in females compared to males 7day-post-IR. Inhibition of apoptosis with ZVAD-FMK treatment prevented IR-induced renal cell death (TUNEL positive; P Zvad =0.04) and tubular damage (P Zvad =0.02) and improved renal function (Pcr: P Zvad =0.027) in females. However, treatment with ZVAD-FMK did not significantly reduced IR-induced renal cell death (TUNEL positive: P sex =0.07; P sex*Zvad= 0.05), tubular damage (P sex =0.99; P sex*Zvad =0.012) or plasma creatinine (P sex =0.085; P sex*Zvad =0.0029) in males 7-days post IR. In conclusion, our data demonstrate that inhibiting apoptosis reduced renal injury and enhanced recovery following IR more effectively in females than in males. Work is supported by NIH U54KL169191 and 5R01DK134695 to JCS. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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