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Abstract: PO0427

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

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Mohamed, Riyaz, Augusta University, Augusta, Georgia, United States
  • O'Connor, Paul, Augusta University, Augusta, Georgia, United States
  • Sullivan, Jennifer C., Augusta University, Augusta, Georgia, United States
Background

Acute kidney injury (AKI) due to ischemia-reperfusion (IR) is a serious and frequent complication with high mortality rates. The mechanisms mediating renal IR injury leading to increased risk of later developing cardiovascular and renal diseases in either sex remain poorly understood, although elevated 12/15-LOX activity has been reported to contribute to the progression of numerous kidney diseases. The goal of the current study was to test the hypothesis that enhanced activation of 12/15-LOX leading to impaired recovery post-IR.

Methods

13-week old male and female SHR were subjected to sham or 30-minute warm bilateral IR (n=6/group). Additional male SHR 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 post-IR. Blood and urine were collected from all rats 24 hrs and 7 days after IR; kidneys were harvested 7 days post-IR for biochemical, histological, and Western blot analysis.

Results

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 greater tubular damage (PIR=0.0003, Psex*IR=0.0019) and renal cell death (PIR=0.001; Psex*IR=0.001) in male vs. female SHR. Delayed recovery of renal function in male SHR was associated with activation of renal 12/15-LOX (PIR<0.05; Psex*IR=0.008), increased lipid peroxidation (PIR=0.008; Psex*IR=0.018), and ER stress (PIR=0.05; Psex*IR=0.01) compared to sham-controls. Pre-treatment of male SHR with ML355 reduced IR-induced lipid peroxidation (PIR*TxT =0.02) and ER stress (PIR*TxT =0.05), prevented IR-induced tubular damage (PIR*TxT=0.02) and tubular cell death (PIR*TxT=0.04), and improved renal function (Pcr: PIR*TxT =0.0067; BUN: PIR*TxT =0.042) compared to vehicle-treated IR males 7 days post-IR.

Conclusion

In conclusion, our data demonstrate that enhanced activation of 12/15-LOX contributes to impaired renal recovery post-IR via ER stress and cell death in male SHR.

Funding

  • Other NIH Support