Catalase deficiency renders remnant kidneys more susceptible to oxidant tissue injury and renal fibrosis in mice.
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(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)) 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 alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta1 (TGF-beta1), 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.


CONCLUSIONS
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.
Kobayashi
Mizuho
M
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Sugiyama
Hitoshi
H
Wang
Da-Hong
DH
Toda
Naomi
N
Maeshima
Yohei
Y
Yamasaki
Yasushi
Y
Masuoka
Noriyoshi
N
Yamada
Masao
M
Kira
Shohei
S
Makino
Hirofumi
H
D000419:Albuminuria / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure; D001835:Body Weight; D002374:Catalase / Q000235:genetics* / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D024141:Collagen Type IV / Q000235:genetics; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005979:Glutathione Peroxidase / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D009392:Nephrectomy; D009929:Organ Size; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism
D000975:Antioxidants; D024042:Collagen Type I; D024141:Collagen Type IV; D003497:Cyclic N-Oxides; D013113:Spin Labels; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C001803:tempol