SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice.
Superoxide dismutase (SOD) is a major defender against excessive superoxide generated under hyperglycemia. We have recently reported that renal SOD1 (cytosolic CuZn-SOD) and SOD3 (extracellular CuZn-SOD) isoenzymes are remarkably down-regulated in KK/Ta-Ins2(Akita) diabetic mice, which exhibit progressive diabetic nephropathy (DN), but not in DN-resistant C57BL/6- Ins2(Akita) (C57BL/6-Akita) diabetic mice. To determine the role of SOD1 and SOD3 in DN, we generated C57BL/6-Akita diabetic mice with deficiency of SOD1 and/or SOD3 and investigated their renal phenotype at the age of 20 weeks. Increased glomerular superoxide levels were observed in SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice but not in SOD1(+/+)SOD3(-/-) C57BL/6-Akita mice. The SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice exhibited higher glomerular filtration rate, increased urinary albumin levels, and advanced mesangial expansion as compared with SOD1(+/+)SOD3(+/+) C57BL/6-Akita mice, yet the severity of DN did not differ between the SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita groups. Increased renal mRNA expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF), reduced glomerular nitric oxide (NO), and increased renal prostaglandin E2 (PGE2) production were noted in the SOD1(-/-)SOD3(+/+) and SOD1(-/-)SOD3(-/-) C57BL/6-Akita mice. This finding indicates that such renal changes in fibrogenic cytokines, NO, and PGE2, possibly caused by superoxide excess, would contribute to the development of overt albuminuria by promoting mesangial expansion, endothelial dysfunction, and glomerular hyperfiltration. The present results demonstrate that deficiency of SOD1, but not SOD3, increases renal superoxide in the setting of diabetes and causes overt renal injury in nephropathy-resistant diabetic mice, and that SOD3 deficiency does not provide additive effects on the severity of DN in SOD1-deficient C57BL/6-Akita mice.
Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. hirofuji@gipc.akita-u.ac.jp
Hiroki
H
Fujita
Hiromi
H
Fujishima
Keiko
K
Takahashi
Takehiro
T
Sato
Tatsunori
T
Shimizu
Tsukasa
T
Morii
Takahiko
T
Shimizu
Takuji
T
Shirasawa
Zhonghua
Z
Qi
Matthew D
MD
Breyer
Raymond C
RC
Harris
Yuichiro
Y
Yamada
Takamune
T
Takahashi
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D015153:Blotting, Western; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000503:physiopathology*; D015232:Dinoprostone / Q000378:metabolism; D005919:Glomerular Filtration Rate; D005920:Glomerular Mesangium / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D060888:Real-Time Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C526318:CCN2 protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D009569:Nitric Oxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015232:Dinoprostone