Inhibition of 12/15 Lipoxygenase (12/15 LOX) Improves Renal Recovery and Function Post Renal Ischemia Reperfusion (IR) injury in Male Spontaneous Hypertensive Rats (SHR)

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Acute kidney injury (AKI) due to ischemia reperfusion (IR) is a serious complication in clinical settings and the male gender is often associated with greater severity and mortality following AKI vs. age-matched females. Recent clinical and basic science studies further suggest that renal ischemic injury increases the likelihood of developing hypertension and hypertensive subjects are likely to have greater AKI severity. Despite the widespread prevalence of hypertension and AKI, what mediates renal IR injury leading to increased risk of later developing cardiovascular and renal diseases in either sex is poorly understood. Elevated 12/15-LOX activity has been reported in hypertension and in many kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15-LOX in hypertensive males results in greater increases in endoplasmic reticulum (ER) stress and tubular cell death leading to impaired post recovery compared females following renal IR. 13-week old male and female SHR were subjected to sham or 30-minute warm bilateral IR (n=6/group). Blood and urine were collected 24 hrs and 7 days after IR; kidneys were harvested 7 days post-IR for biochemical, histological, and Western blot analysis. IR increased plasma creatinine (Pcr) and blood urea nitrogen (BUN) in both male and female SHR compared to respective sham controls at 24 hrs (PIR =0.0001; Psex*IR=0.2). At 7 days post-IR, Pcr and BUN remained elevated in male SHR but returned to baseline levels in females (Pcr: PIR =0.03; Psex*IR=0.04; BUN: PIR <0.05; Psex*IR=0.05). Histological examination of kidneys 7 days post-IR showed increases in damaged tubules (PIR=0.0003, Psex*IR=0.0019) and tubular cell death (PIR=0.001; Psex*IR=0.001) in males vs. females SHR. Delayed recovery of renal function in male SHR was associated with an upregulation of renal 12/15-LOX protein (PIR<0.05; Psex*IR=0.008), increased lipid peroxidation (PIR=0.008; Psex*IR=0.018), and ER stress protein levels (PIR=0.05; Psex*IR=0.01) compared to sham-controls. To assess the contribution of 12/15 LOX on impaired recovery from IR in male SHR, additional rats were randomized to receive vehicle or the specific 12/15-LOX inhibitor ML355 (30 mg/kg i.p.; n=5/group) 1 hr prior to sham/IR and every other day up to 7 days. Treatment with ML355 1) reduced lipid peroxidation (PIR*TxT =0.02) and ER stress protein levels (PIR*TxT =0.05), 2) prevented IR-induced tubular damage (PIR*TxT=0.02) and tubular cell death (PIR*TxT=0.04), and 3) improved renal function (Pcr: PIR*TxT =0.0067; BUN: PIR*TxT =0.042) compared to vehicle-treated males following IR. In conclusion, our data demonstrate that enhanced activation of 12/15-LOX in the kidney contributes to impaired renal recovery post-IR in male SHR.