کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5903598 | 1157100 | 2012 | 11 صفحه PDF | دانلود رایگان |
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-Ins2Akita diabetic mice, which exhibit progressive diabetic nephropathy (DN), but not in DN-resistant C57BL/6- Ins2Akita (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 SOD1â/âSOD3+/+ and SOD1â/âSOD3â/â C57BL/6-Akita mice but not in SOD1+/+SOD3â/â C57BL/6-Akita mice. The SOD1â/âSOD3+/+ and SOD1â/âSOD3â/â 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 SOD1â/âSOD3+/+ and SOD1â/âSOD3â/â 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 SOD1â/âSOD3+/+ and SOD1â/âSOD3â/â 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.
Journal: Metabolism - Volume 61, Issue 12, December 2012, Pages 1714-1724