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PO1-3-1

BENEFICAL EFFECTS OF BARDOXOLONE METHYL, A NRF2 ACTIVATOR, ON ACETAMINOPHEN-INDUCED ACUTE NEPHROTOXICITY IN RATS

[Speaker] Emine Kadioglu:1
[Co-author] Yasemin Teksen:2, Fikriye Y. Ozatik:2, Orhan Ozatik:3, Zeynep Bayat:4
1:Emergency, Dumlupinar University Faculty of Medicine, Turkey, 2:Pharmacology, Dumlupinar University Faculty of Medicine, Turkey, 3:Histology and Embyrology, Dumlupinar University Faculty of Medicine, Turkey, 4:Biology, Dumlupinar University Art and Science Faculty, Turkey

Objectives. Bardoxolone-methyl (BM) is an antioxidant and antiinflamatory agent that acts through induction of the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway. BM improves the renal function in chronic kidney disease and type 2 diabetes. Acetaminophen (APAP), used as an analgesic and antipyretic, produces acute liver and kidney failure at high doses. In this study, effect of BM on APAP-induced acute kidney injury and possible mechanism of it's renal protective effect were investigated in rats.
Methods. Rats were divided into six group (n=7): Control (saline, oral), APAP + sesame oil (vehicle of BM, oral), APAP + NAC (N-acetyl sistein 160 mg/kg oral), APAP + BM (5 and 10 mg/kg oral). Nephrotoxicity was induced by the administration of a single dose of 2 g/kg APAP orally. One hour before APAP administration, rats were received single dose of NAC and BM. The rats were sacrificed 24 h after the administration of APAP. KIM-1 (Kidney Injury Molecule-1), NGAL (neutrophil gelatinase-associated lipocalin), TNF-alfa (Tumor necrosis factor-alfa), TGF-beta (Transforming growth factor-beta) were measured by ELISA in rat kidney homogenates. Tissue total oxidant status (TOS), and total antioxidant status (TAS) were evaluated spectrofotometrically. Apoptosis was assessed by TUNEL method. Glomerular and tubular structures were also examined histopathologically.
Results. APAP administration caused elevated levels of renal KIM-1, NGAL, TNF-alfa, TGF-beta, TOS and decreased TAS. Treatment with BM prevented APAP-induced nephrotoxicity as evidenced by significantly reduced renal KIM-1, NGAL, TNF-alfa, TGF-beta, TOS and increased TAS levels dose-dependent. BM was normalized the altered renal morphology and apoptosis. The benefical effects of BM on APAP-induced nephrotoxicity were similar to NAC.
Conclusions. Our results showed that BM could reduce APAP-induced nephrotoxicity via anti-inflammatory, anti-oxidant, and anti-apoptotic effects.

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