SOD1, but not SOD3, deficiency accelerates diabetic renal injury in
C57BL/6-Ins2(Akita) diabetic mice.
Authors Fujita H, Fujishima H, Takahashi K, Sato T, Shimizu T, Morii T, Shimizu T,
Shirasawa T, Qi Z, Breyer MD, Harris RC, Yamada Y, Takahashi T
Submitted By Takamune Takahashi on 1/30/2013
Status Published
Journal Metabolism: clinical and experimental
Year 2012
Date Published 12/1/2012
Volume : Pages 61 : 1714 - 1724
PubMed Reference 22632894
Abstract 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-ß1 (TGF-ß1) 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.


Investigators with authorship
NameInstitution
Matthew BreyerEli Lilly and Company
Raymond HarrisVanderbilt University
Takamune TakahashiVanderbilt University

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