Inhibition of xanthine oxidoreductase protects against contrast-induced renal tubular injury by activating adenosine monophosphate-activated protein kinase

• Published in: Free radical biology & medicine 2019-12, Vol.145, p.209-220
• Main Authors: Yang, Keum-Jin, Kim, Jeong Ho, Chang, Yoon Kyung, Park, Cheol Whee, Kim, Suk Young, Hong, Yu Ah
• Format: Article
• Language: English
• Subjects: Acute kidney injury; AMPK; Contrast media; Febuxostat; Oxidative stress
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2019.09.027

Reactive oxygen species (ROS) play a pivotal role in the development of contrast-induced nephropathy (CIN). The inhibition of xanthine oxidoreductase is known to reduce levels of ROS. We investigated whether febuxostat could attenuate oxidative stress via the activation of adenosine monophosphate-activated protein kinase (AMPK) against CIN. In a mouse model of CIN, renal impairment and tubular injury substantially increased, whereas febuxostat attenuated renal injury. Plasma and kidney xanthine oxidoreductase levels were decreased by febuxostat. Febuxostat administration was accompanied by the upregulation of AMPK phosphorylation and the inhibition of nicotinamide-adenine dinucleotide phosphate oxidase (Nox)1 and Nox2, followed by the inhibition of hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 expressions and the suppression of transcription factor forkhead box O (FoxO)1 and FoxO3a phosphorylation. Cell survival was significantly reduced after iohexol administration and febuxostat ameliorated iohexol-induced cell death in proximal tubular (HK-2) cells. Furthermore, febuxostat enhanced AMPK phosphorylation and inhibited Nox1, Nox2, and HIF-1α expression in iohexol-exposed HK-2 cells. Finally, these processes decrease ROS in both in vivo and in vitro models of CIN. AMPK inhibition using small interfering RNA blunted the antioxidative effects of febuxostat in iohexol-treated HK-2 cells. Febuxostat attenuated CIN by modulating oxidative stress through AMPK–NADPH oxidase–HIF-1α signaling. [Display omitted] •Hyperuricemia is an independent risk factor for CIN, and increased XOR is associated with elevated ROS.•CIN is accompanied by increased XOR, which is related to a decreased level of AMPK phosphorylation.•The inhibition of XOR by febuxostat pretreatment protects against iohexol-induced tubular cell death and tubular injury.•Febuxostat attenuates CIN by modulating oxidative stress through AMPK–NADPH oxidase–HIF-1α signaling.