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Abstract
Increased NAD(P)H oxidase-dependent free radical generation has been proposed to be a mechanism in glycerol-induced acute renal failure (ARF). Previously, we showed a PPARγ-mediated regulation of free radical generation in ARF. In this study, we examined NAD(P)H oxidase-dependent pathology in ARF and its connection with PPARγ using both Sprague–Dawley rats and gp91phox (+/−) mice. Male gp91phox (+/−) or wild type (+/+) mice were distributed into vehicle and ARF group (50% glycerol; 8 mL/kg bw; i.m.). Animals were placed in metabolic cages for 24 hr and were sacrificed under pentobarbital anesthesia. Urine, plasma and kidneys were processed for biochemical and molecular analysis. Glycerol doubled proteinuria in (+/+) mice (68 ± 4 mg/24 hr) but not in (+/−) mice (43 ± 9 mg/24 hr). This was associated with a markedly reduced creatinine excretion in (+/+) mice (Con: 0.6 ± 0.03 & ARF: 0.37 ± 0.02). Basal plasma and urinary NO was higher in (+/−) mice than the (+/+) type while plasma 8-isoprostane level was lower in (+/−) mice (WT: 165 ± 20; KO: 100 ± 15 pg/mL). Glycerol reduced UNOXV in both (+/+) and (+/−) mice although plasma NO was unchanged. Glycerol also doubled 8-isoprostane in (+/+) (363 ± 22 pg/mL) but not in (+/−) mice (152 ± 20 pg/mL) and this was associated with an increased NAD(P)H oxidase activity in the (+/+) mice. In ARF, PPARγ expression was reduced in (+/+) mice but increased in (+/−) mice. PPARγ activity was also reduced in (+/+) mice but was unchanged in (+/−) mice. We conclude that gp91phox contributes to NAD(P)H oxidase-mediated increased free radical generation in ARF and this may be via reduced PPARγ.