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Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides
Kentaro Fujii, … , Hiroshi Itoh, Makoto Suematsu
Kentaro Fujii, … , Hiroshi Itoh, Makoto Suematsu
Published November 14, 2019
Citation Information: JCI Insight. 2019;4(22):e124816. https://doi.org/10.1172/jci.insight.124816.
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Categories: Research Article Nephrology Therapeutics

Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides

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Abstract

Although oxidative stress plays central roles in postischemic renal injury, region-specific alterations in energy and redox metabolism caused by short-duration ischemia remain unknown. Imaging mass spectrometry enabled us to reveal spatial heterogeneity of energy and redox metabolites in the postischemic murine kidney. After 10-minute ischemia and 24-hour reperfusion (10mIR), in the cortex and outer stripes of the outer medulla, ATP substantially decreased, but not in the inner stripes of the outer medulla and inner medulla. 10mIR caused renal injury with elevation of fractional excretion of sodium, although histological damage by oxidative stress was limited. Ischemia-induced NADH elevation in the cortex indicated prolonged production of reactive oxygen species by xanthine oxidase (XOD). However, consumption of reduced glutathione after reperfusion suggested the amelioration of oxidative stress. An XOD inhibitor, febuxostat, which blocks the degradation pathway of adenine nucleotides, promoted ATP recovery and exerted renoprotective effects in the postischemic kidney. Because effects of febuxostat were canceled by silencing of the hypoxanthine phosphoribosyl transferase 1 gene in cultured tubular cells, mechanisms for the renoprotective effects appear to involve the purine salvage pathway, which uses hypoxanthine to resynthesize adenine nucleotides, including ATP. These findings suggest a novel therapeutic approach for acute ischemia/reperfusion renal injury with febuxostat through salvaging high-energy adenine nucleotides.

Authors

Kentaro Fujii, Akiko Kubo, Kazutoshi Miyashita, Masaaki Sato, Aika Hagiwara, Hiroyuki Inoue, Masaki Ryuzaki, Masanori Tamaki, Takako Hishiki, Noriyo Hayakawa, Yasuaki Kabe, Hiroshi Itoh, Makoto Suematsu

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Figure 7

Febuxostat promoted ATP recovery after oxygen and glucose deprivation in cultured tubular cells.

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Febuxostat promoted ATP recovery after oxygen and glucose deprivation in...
(A) Scheme of the nucleoside salvage pathway. Asterisk means stable isotope–labeled metabolites. (B) Scheme of the present study. HK-2 cells were exposed to hypoxia (5% CO2, 1% O2) for 12 hours followed by 16 hours of reoxygenation (5% CO2, 21% O2). During hypoxia, the culture medium was replaced with DMEM containing no glucose (OGD). During reoxygenation, the culture medium was replaced with DMEM containing glucose, 10% FBS, and 100 μM labeled hypoxanthine-13C2,15N. (C) The contents of ATP and labeled ATP were measured from cell lysates. (D) The contents of total adenylates (ATP + ADP + AMP) and labeled total adenylates. ##P < 0.01. n = 6 for each group. Differences in mean values were statistically analyzed by Student’s 2-tailed t test. HPRT1, hypoxanthine phosphoribosyl transferase 1.
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