PPARγ and NAD(P)H oxidase system interaction in glycerol-induced acute renal failure: role ofgp91phoxsubunit of NAD(P)H oxidase

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 PPARgmediated regulation of free radical generation in ARF. In this study, we examined NAD(P)H oxidase-dependent pathology in ARF and its connection with PPARg using both SpragueDawley rats and gp91phox (+/À) mice. Male gp91phox (+/À) 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 (+/À) 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 (+/À) mice than the (+/+) type while plasma 8-isoprostane level was lower in (+/À) mice (WT: 165 ± 20; KO: 100 ± 15 pg/mL). Glycerol reduced UNO X V in both (+/+) and (+/À) mice although plasma NO was unchanged. Glycerol also doubled 8-isoprostane in (+/+) (363 ± 22 pg/mL) but not in (+/À) mice (152 ± 20 pg/mL) and this was associated with an increased NAD(P)H oxidase activity in the (+/+) mice. In ARF, PPARg expression was reduced in (+/+) mice but increased in (+/À) mice. PPARg activity was also reduced in (+/+) mice but was unchanged in (+/À) mice. We conclude that gp91phox contributes to NAD(P)H oxidase-mediated increased free radical generation in ARF and this may be via reduced PPARg.

Açai berry extract attenuates glycerol-induced acute renal failure in rats

“…3 The pathogenesis of glycerol-induced ARF is still not completely understood, but it is generally believed that it may involve oxidative stress and decreased renal blood flow. 4,5 Oxidative stress occurs as a result of iron released from heme group of myoglobin. Iron induces the formation of reactive oxygen species that leads to lipid peroxidation and cellular death.…”

Stevioside protects against rhabdomyolysis‐induced acute kidney injury through PPAR‐γ agonism in rats

“…PPAR‐γ increases nitric oxide levels by activating endothelial nitric oxide synthase enzyme, which results in renal vasodilatation (Singh et al, 2019). Notably, glycerol‐induced AKI has been attributed to increased NADPH oxidase dependent free radical generation and reduced PPAR‐γ expression (Newaz & Yousefipour, 2014).…”

“…An interesting finding of our study is that the anti‐oxidant effect of stevioside was abolished by BADGE treatment in rats, which clearly indicates that PPAR‐γ plays an essential role in stevioside mediated anti‐oxidant effect. PPAR‐γ activation has been known to down‐regulate NADPH oxidase and consequent production of free radicals (Fong, Tsai, Chen, Wu, & Lin, 2010; Newaz & Yousefipour, 2014). In addition, PPAR‐γ regulates the transcription and gene expression of anti‐oxidant enzymes such as superoxide dismutase and catalase (Fong et al, 2010).…”