Greater necrosis following renal ischemia–reperfusion (IR) in males impairs post-IR recovery compared to females

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 are 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. Our lab previously demonstrated that despite similar levels of renal injury post-IR, male Sprague-Dawley (SD) rats exhibited greater necrosis 24 hrs following IR compared to female SD rats. The goal of the current study was to test the hypothesis that greater renal necrotic cell death in males contributes to delayed recovery following renal IR compared to females. 13-wk-old male and female SD rats were randomized to sham, 50-minute warm bilateral IR + vehicle, or 50-minute warm bilateral IR + Necrox-5, a cell permeable necrosis inhibitor (1 mg/kg/day, ip). Blood was collected from all rats 1- and 7-days post-IR. All rats were euthanized for 7-days post-IR, and kidneys and blood were collected. Plasma creatinine and BUN were measured via Quantichrome kits to assess renal function, renal tubular injury was measured via H Psex*IR=0.92) and BUN (PIR =0.001; Psex*IR=0.19) following IR vs sham controls at 24 hrs and remain elevated at 7 days post-IR in both sexes (Pcr: PIR =0.0001; Psex*IR=0.07; BUN: 0.021; Psex*IR=0.089). Interestingly, impaired kidney function in males was associated with greater renal necrosis (Psex=0.001; Psex*IR=0.05), renal HMGB1 protein levels and PARP-1 activity (Psex=0.001; Psex*IR=0.007) compared to females 7 days-post-IR. Inhibition of necrosis with Necrox-5 treatment prevented IR-induced increases in renal necrosis (TUNEL positive; PNex5=0.03; Psex*Nex5=0.05), renal PARP-1 activity (PNex5=0.06; Psex*Nex5=0.042), and tubular damage (PNex5=0.02; Psex*Nex5=0.012) and improved renal function (Pcr: PNex5 =0.027; Psex*Nex5=0.0029: BUN: PNex5 =0.041; Psex*Nex5=0.029) in males. Necrox-5 did not significantly alter IR-induced renal cell death (TUNEL positive: Psex=0.067), PARP-1 activity (Psex=0.069), tubular damage (Psex=0.99), and PCr (Psex=0.055;) or BUN (Psex=0.033;) in females 7-days post IR. In conclusion, our data demonstrated that necrosis contributes to delayed renal recovery and greater tubular injury following IR in male compared to female SD rats. This abstract was presented at the American Physiology Summit 2026 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.