Catalase deficiency renders remnant kidneys more susceptible to oxidant tissue injury and renal fibrosis in mice

Mizuho Kobayashi, Hitoshi Sugiyama, Da Hong Wang, Naomi Toda, Yohei Maeshima, Yasushi Yamasaki, Noriyoshi Masuoka, Masao Yamada, Shohei Kira, Hirofumi Makino

研究成果査読

83 被引用数 (Scopus)

抄録

Background. Catalase is one of the important antioxidant enzymes regulating the levels of intracellular hydrogen peroxide and hydroxyl radical. The effect of catalase deficiency on progressive renal fibrosis has not been fully elucidated. Methods. Homozygous acatalasemic mutant mice (C3H/ AnLCs bCsb) and control wild-type mice (C3H/AnLCs aCsa) were subjected to 5/6 nephrectomy. The functional and morphological alterations of the remnant kidneys, including tubulointerstitial fibrosis, epithelial to mesenchymal transition (EMT), peroxidation, antioxidant enzyme activity, and gene expression of EMT-related molecules were compared between the two groups at 6, 12, and 18 weeks after 5/6 nephrectomy. Results. The 5/6 nephrectomy resulted in albuminuria, decreased renal function, and tubulointerstitial fibrosis with accumulation of type I and type IV collagens in the remnant kidneys of both mouse groups. However, the degree of these changes was significantly higher in acatalasemic mice after 5/6 nephrectomy as compared with wild-type mice until week 18. EMT, a crucial phenotypic alteration of tubular epithelial cells, was observed in acatalasemic mice by electron microscopy and was associated with upregulation of EMT-related α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and fibroblast specific protein-1 (FSP-1) gene expression. Significant increases in the tubulointerstitial deposition of lipid peroxidation products, including 4-hydroxy-2-nonenal and urinary excretion of 8-hydroxy-2′- deoxyguanosine were observed in the acatalasemic mice after 5/6 nephrectomy as compared with the wild-type mice. Glomerular sclerosis developed after tubulointerstitial injury in acatalasemic mice. The level of catalase activity remained low in the remnant kidneys of acatalasemic mice until week 18 without compensatory up-regulation of glutathione peroxidase or superoxide dismutase (SOD) activity. Finally, supplementation of a SOD mimetic tempol did not prevent peroxidation and tubulointerstitial fibrosis in the acatalasemic remnant kidneys. Conclusion. These findings indicate that acatalasemia exacerbates renal oxidant tissue injury and sensitizes remnant kidneys to EMT and progressive renal fibrosis. This study suggests a central role for catalase in the defense against oxidant-mediated renal fibrosis.

本文言語English
ページ(範囲)1018-1031
ページ数14
ジャーナルKidney International
68
3
DOI
出版ステータスPublished - 9月 2005
外部発表はい

ASJC Scopus subject areas

  • 腎臓病学

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