Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules

Toshio Ohtsubo, Kiyoshi Matsumura, Kanae Sakagami, Koji Fujii, Kazuhiko Tsuruya, Hideko Noguchi, Ilsa I. Rovira, Toren Finkel, Mitsuo Iida

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species production, and adipogenesis. XOR gene-disrupted (XOR-/-) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR-/- mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR-/- mice was accompanied by deposition of crystals and lipid-rich substances. Triglyceride content in renal homogenates was significantly increased in XOR-/- mice. The level of lipogenesis-related gene expression was comparable in XOR +/+and XOR-/- mice, whereas the expression of adipogenesis-related gene expression was significantly elevated in XOR-/- mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR -/- mice. mmunohistochemical analysis, Western blotting, and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia, and oxidative stress were increased in XOR-/- mice. Finally, we demonstrate that primary renal epithelial cells from XOR-/- mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in the renal tubules. We believe that these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia, and reactive oxygen species production, ultimately resulting in renal failure through increased renal interstitial fibrosis.

Original languageEnglish
Pages (from-to)868-876
Number of pages9
JournalHypertension
Volume54
Issue number4
DOIs
Publication statusPublished - Oct 1 2009

Fingerprint

Xanthine Dehydrogenase
Fibrosis
Kidney
Lipids
Adipogenesis
Hypoxanthine
Xanthine
purine
Renal Insufficiency
Reactive Oxygen Species
Triglycerides
Inflammation
Gene Expression
Lipogenesis
Epithelial-Mesenchymal Transition
Myofibroblasts
Uric Acid

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules. / Ohtsubo, Toshio; Matsumura, Kiyoshi; Sakagami, Kanae; Fujii, Koji; Tsuruya, Kazuhiko; Noguchi, Hideko; Rovira, Ilsa I.; Finkel, Toren; Iida, Mitsuo.

In: Hypertension, Vol. 54, No. 4, 01.10.2009, p. 868-876.

Research output: Contribution to journalArticle

Ohtsubo, T, Matsumura, K, Sakagami, K, Fujii, K, Tsuruya, K, Noguchi, H, Rovira, II, Finkel, T & Iida, M 2009, 'Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules', Hypertension, vol. 54, no. 4, pp. 868-876. https://doi.org/10.1161/HYPERTENSIONAHA.109.135152
Ohtsubo, Toshio ; Matsumura, Kiyoshi ; Sakagami, Kanae ; Fujii, Koji ; Tsuruya, Kazuhiko ; Noguchi, Hideko ; Rovira, Ilsa I. ; Finkel, Toren ; Iida, Mitsuo. / Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules. In: Hypertension. 2009 ; Vol. 54, No. 4. pp. 868-876.
@article{8861324de4f043879163f56ea6781eae,
title = "Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules",
abstract = "Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species production, and adipogenesis. XOR gene-disrupted (XOR-/-) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR-/- mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR-/- mice was accompanied by deposition of crystals and lipid-rich substances. Triglyceride content in renal homogenates was significantly increased in XOR-/- mice. The level of lipogenesis-related gene expression was comparable in XOR +/+and XOR-/- mice, whereas the expression of adipogenesis-related gene expression was significantly elevated in XOR-/- mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR -/- mice. mmunohistochemical analysis, Western blotting, and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia, and oxidative stress were increased in XOR-/- mice. Finally, we demonstrate that primary renal epithelial cells from XOR-/- mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in the renal tubules. We believe that these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia, and reactive oxygen species production, ultimately resulting in renal failure through increased renal interstitial fibrosis.",
author = "Toshio Ohtsubo and Kiyoshi Matsumura and Kanae Sakagami and Koji Fujii and Kazuhiko Tsuruya and Hideko Noguchi and Rovira, {Ilsa I.} and Toren Finkel and Mitsuo Iida",
year = "2009",
month = "10",
day = "1",
doi = "10.1161/HYPERTENSIONAHA.109.135152",
language = "English",
volume = "54",
pages = "868--876",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules

AU - Ohtsubo, Toshio

AU - Matsumura, Kiyoshi

AU - Sakagami, Kanae

AU - Fujii, Koji

AU - Tsuruya, Kazuhiko

AU - Noguchi, Hideko

AU - Rovira, Ilsa I.

AU - Finkel, Toren

AU - Iida, Mitsuo

PY - 2009/10/1

Y1 - 2009/10/1

N2 - Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species production, and adipogenesis. XOR gene-disrupted (XOR-/-) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR-/- mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR-/- mice was accompanied by deposition of crystals and lipid-rich substances. Triglyceride content in renal homogenates was significantly increased in XOR-/- mice. The level of lipogenesis-related gene expression was comparable in XOR +/+and XOR-/- mice, whereas the expression of adipogenesis-related gene expression was significantly elevated in XOR-/- mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR -/- mice. mmunohistochemical analysis, Western blotting, and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia, and oxidative stress were increased in XOR-/- mice. Finally, we demonstrate that primary renal epithelial cells from XOR-/- mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in the renal tubules. We believe that these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia, and reactive oxygen species production, ultimately resulting in renal failure through increased renal interstitial fibrosis.

AB - Xanthine oxidoreductase (XOR) is an enzyme responsible for purine degradation, reactive oxygen species production, and adipogenesis. XOR gene-disrupted (XOR-/-) mice demonstrate renal failure and early death within several months. The aim of this study was to elucidate the mechanism of renal damage in XOR-/- mice and to determine the physiological role of XOR in the kidney. Histological analysis revealed that renal tubular damage in XOR-/- mice was accompanied by deposition of crystals and lipid-rich substances. Triglyceride content in renal homogenates was significantly increased in XOR-/- mice. The level of lipogenesis-related gene expression was comparable in XOR +/+and XOR-/- mice, whereas the expression of adipogenesis-related gene expression was significantly elevated in XOR-/- mice. Urinary excretions of xanthine and hypoxanthine were markedly elevated in XOR -/- mice. mmunohistochemical analysis, Western blotting, and real time RT-PCR revealed that various markers of fibrosis, inflammation, ischemia, and oxidative stress were increased in XOR-/- mice. Finally, we demonstrate that primary renal epithelial cells from XOR-/- mice are more readily transformed to myofibroblasts, which is a marker of increased epithelial mesenchymal transition. These results suggest that XOR gene disruption induced the depletion of uric acid and the accumulation of triglyceride-rich substances, xanthine, and hypoxanthine in the renal tubules. We believe that these changes contribute to a complex cellular milieu characterized by inflammation, tissue hypoxia, and reactive oxygen species production, ultimately resulting in renal failure through increased renal interstitial fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=70349672857&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349672857&partnerID=8YFLogxK

U2 - 10.1161/HYPERTENSIONAHA.109.135152

DO - 10.1161/HYPERTENSIONAHA.109.135152

M3 - Article

C2 - 19667249

AN - SCOPUS:70349672857

VL - 54

SP - 868

EP - 876

JO - Hypertension

JF - Hypertension

SN - 0194-911X

IS - 4

ER -