PPARγ and NAD(P)H oxidase system interaction in glycerol-induced acute renal failure: role of gp91phox subunit of NAD(P)H oxidase.
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.
College of Pharmacy, Chicago State University , Chicago, IL , USA and.
Mohammad
M
Newaz
Zivar
Z
Yousefipour
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D005609:Free Radicals / Q000378:metabolism; D005990:Glycerol; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic
D005609:Free Radicals; D008562:Membrane Glycoproteins; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D015237:Dinoprost; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C515768:Cyba protein, rat; C060505:neutrophil cytosolic factor 1; D005990:Glycerol; C039671:ciglitazone