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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere124816
JournalJCI Insight
Volume4
Issue number22
DOIs
Publication statusPublished - 2019 Nov 14

Fingerprint

Adenine Nucleotides
Xanthine Oxidase
Kidney
Ischemia
Wounds and Injuries
Reperfusion
Oxidative Stress
Hypoxanthine
Adenosine Triphosphate
Oxidation-Reduction
Transferases
Reperfusion Injury
NAD
Energy Metabolism
Glutathione
Cultured Cells
Reactive Oxygen Species
Mass Spectrometry
Sodium
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides. / Fujii, Kentaro; Kubo, Akiko; Miyashita, Kazutoshi; Sato, Masaaki; Hagiwara, Aika; Inoue, Hiroyuki; Ryuzaki, Masaki; Tamaki, Masanori; Hishiki, Takako; Hayakawa, Noriyo; Kabe, Yasuaki; Itoh, Hiroshi; Suematsu, Makoto.

In: JCI Insight, Vol. 4, No. 22, e124816, 14.11.2019.

Research output: Contribution to journalArticle

Fujii, K, Kubo, A, Miyashita, K, Sato, M, Hagiwara, A, Inoue, H, Ryuzaki, M, Tamaki, M, Hishiki, T, Hayakawa, N, Kabe, Y, Itoh, H & Suematsu, M 2019, 'Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides', JCI Insight, vol. 4, no. 22, e124816. https://doi.org/10.1172/jci.insight.124816
Fujii, Kentaro ; Kubo, Akiko ; Miyashita, Kazutoshi ; Sato, Masaaki ; Hagiwara, Aika ; Inoue, Hiroyuki ; Ryuzaki, Masaki ; Tamaki, Masanori ; Hishiki, Takako ; Hayakawa, Noriyo ; Kabe, Yasuaki ; Itoh, Hiroshi ; Suematsu, Makoto. / Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides. In: JCI Insight. 2019 ; Vol. 4, No. 22.
@article{9541f58a72b147f383c154a58d0767de,
title = "Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides",
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.",
author = "Kentaro Fujii and Akiko Kubo and Kazutoshi Miyashita and Masaaki Sato and Aika Hagiwara and Hiroyuki Inoue and Masaki Ryuzaki and Masanori Tamaki and Takako Hishiki and Noriyo Hayakawa and Yasuaki Kabe and Hiroshi Itoh and Makoto Suematsu",
year = "2019",
month = "11",
day = "14",
doi = "10.1172/jci.insight.124816",
language = "English",
volume = "4",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "22",

}

TY - JOUR

T1 - Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides

AU - Fujii, Kentaro

AU - Kubo, Akiko

AU - Miyashita, Kazutoshi

AU - Sato, Masaaki

AU - Hagiwara, Aika

AU - Inoue, Hiroyuki

AU - Ryuzaki, Masaki

AU - Tamaki, Masanori

AU - Hishiki, Takako

AU - Hayakawa, Noriyo

AU - Kabe, Yasuaki

AU - Itoh, Hiroshi

AU - Suematsu, Makoto

PY - 2019/11/14

Y1 - 2019/11/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85077398207&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85077398207&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.124816

DO - 10.1172/jci.insight.124816

M3 - Article

C2 - 31723053

AN - SCOPUS:85077398207

VL - 4

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 22

M1 - e124816

ER -