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

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 (US)
Pages (from-to)868-876
Number of pages9
JournalHypertension
Volume54
Issue number4
DOIs
StatePublished - Oct 2009
Externally publishedYes

Keywords

  • Epithelial mesenchymal transition
  • Lipid
  • Oxidative stress
  • Renal interstitial fibrosis
  • Uric acid
  • Xanthine
  • Xanthine oxidoreductase

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Ohtsubo, T., Matsumura, K., Sakagami, K., Fujii, K., Tsuruya, K., Noguchi, H., Rovira, I. I., Finkel, T., & Iida, M. (2009). Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules. Hypertension, 54(4), 868-876. https://doi.org/10.1161/HYPERTENSIONAHA.109.135152