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Nrf2 antioxidant pathway activation attenuates renal ischemia/reperfusion (I/R)‐induced alterations in biomarkers
Author(s) -
Richards Toni L.,
Ida Kevin K.,
Horn Todd R.,
Kandlikar Sachin S.,
Plato Craig F.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.704.12
Subject(s) - urinary system , urine , kidney , proteinuria , excretion , oxidative stress , medicine , acute kidney injury , ischemia , antioxidant , chemistry , urology , renal ischemia , endocrinology , pharmacology , reperfusion injury , biochemistry
Acute kidney injury (AKI) secondary to acute renal ischemia is associated with high mortality and morbidity. Oxidative stress is a key component of renal I/R injury making the Nrf2 antioxidant pathway a target to lessen AKI. We evaluated bardoxolone methyl's (BARD) ability to activate the Nrf2 pathway and attenuate I/R‐induced urine biomarkers. At d‐2, rats received (po, bid for study duration) vehicle (Veh) or BARD (0.3, 1, 3, or 30 mg/kg). At d0, rats underwent sham (n=6) or 40 min of warm, bilateral renal I/R (n=10/group) surgery using our proprietary vascular clamp. Rats were single‐housed in metabolic cages for balance of study. 24 and 48 hrs post‐reperfusion, urine volumes were determined and sampled. Clinical chemistry and ELISAs were applied to urine analysis; renal mRNA was quantitated using Luminex. BARD increased renal cortical Nqo1 mRNA expression (917% vs. Veh) indicating Nrf2 pathway activation. I/R increased proteinuria by 728% at 24 hrs relative to sham. 0.3–3 mg/kg BARD attenuated I/R‐induced proteinuria (avg. of 57% vs. Veh). I/R timedependently increased urinary Kim‐1 (4843% at 48 hrs) and NGAL (2962% at 48 hrs) excretion compared to sham. 1 and 3 mg/kg BARD attenuated I/R‐induced increases in Kim‐1 (57% and 93% vs. Veh, respectively) and NGAL (65% and 81% vs. Veh, respectively) excretion. In conclusion, Nrf2 pathway activation effectively inhibits I/R‐induced increases in urinary AKI biomarkers.