SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2Akita diabetic mice

被引：43

作者：

Fujita, Hiroki ^{[1
,2
]}

Fujishima, Hiromi ^{[1
]}

Takahashi, Keiko ^{[2
]}

Sato, Takehiro ^{[1
]}

Shimizu, Tatsunori ^{[1
]}

Morii, Tsukasa ^{[1
]}

Shimizu, Takahiko ^{[3
]}

Shirasawa, Takuji ^{[3
,4
]}

Qi, Zhonghua ^{[2
]}

Breyer, Matthew D. ^{[2
]}

Harris, Raymond C. ^{[2
]}

Yamada, Yuichiro ^{[1
]}

Takahashi, Takamune ^{[2
]}

机构：

[1] Akita Univ, Grad Sch Med, Div Endocrinol Metab & Geriatr Med, Akita 0108543, Japan

[2] Vanderbilt Univ, Div Nephrol & Hypertens, Med Ctr, Nashville, TN 37232 USA

[3] Tokyo Metropolitan Inst Gerontol, Div Mol Gerontol, Itabashi Ku, Tokyo 1730015, Japan

[4] Juntendo Univ, Dept Aging Control Med, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan

来源：

METABOLISM-CLINICAL AND EXPERIMENTAL | 2012年 / 61卷 / 12期

基金：

美国国家卫生研究院;

关键词：

Akita mouse; Diabetic nephopathy; Knockout mouse; Oxidative stress; Superoxide dismutase; NITRIC-OXIDE SYNTHASE; GLOMERULAR-FILTRATION BARRIER; SUPEROXIDE-DISMUTASE GENE; OXIDATIVE STRESS; CHARGE SELECTIVITY; SIGNALING PATHWAYS; LIPID-PEROXIDATION; ANGIOTENSIN-II; B2; RECEPTORS; NEPHROPATHY;

D O I：

10.1016/j.metabol.2012.05.005

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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 (ON), 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 C57BW6-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 SOD-/-SOD-/- 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 ON did not differ between the SOD1(-/-)SOD3(-/-) and SOD1(-/-)SOD3(-/)- C57BL/6-Akita groups. Increased renal mRNA expression of transforming growth factor-beta 1. (TGF-beta 1) 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. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：1714 / 1724

页数：11

共 60 条

[1]

Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy [J].