SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2 diabetic mice

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-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 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.

Extracellular Superoxide Dismutase Protects against Proteinuric Kidney Disease

“…Whereas one study found that EC-SOD ameliorates ischemic AKI, 15 another study failed to find an effect in a proteinuric diabetic nephropathy model. 17 Although the latter study casts doubt on the importance of EC-SOD, it was unclear whether the result is generalizable to all forms of proteinuric CKD.…”

“…It has previously been shown that intracellular SOD is protective against diabetic nephropathy, 25 although the extracellular isoform was not vital to progression in this disease model. 17 However, the high expression of EC-SOD in the kidney suggests that it plays a key role in maintaining homeostasis. 10 In light of our data, it is now clear that extracellular scavenging of superoxide is necessary in models of proteinuric CKD induced by exposure to ADR, angiotensin II, and albumin overload.…”

“…Furthermore, it is important to note that the earlier diabetic study utilized a mouse that was genetically susceptible to diabetes but is somewhat resistant to the development of diabetic nephropathy. 17 It is possible that the genetic factors underlying this phenotype could have masked any potential effects of EC-SOD.…”

“…15 Another study initially found that diabetic nephropathy in animals is accompanied by a loss of Cu/Zn SOD and EC-SOD, 16 but subsequent investigations failed to show any worsening of disease in EC-SOD null mice. 17 To our knowledge, there are no studies showing an effect of EC-SOD on proteinuric CKD.…”

Aggravation of diabetic nephropathy in BCL-2 interacting cell death suppressor (BIS)-haploinsufficient mice together with impaired induction of superoxide dismutase (SOD) activity

“…Notably, in mice, the overexpression of SOD has been found to abrogate diabetesinduced renal injuries, most likely due to reduced superoxide-NO interactions [9]. In addition, ablation of the Sod1 gene has been found to result in an acceleration of diabetic renal injuries in both STZ-induced C57BL/6 strains and in C57BL/6-Akita strains [34,35]. Recently, a human genetic study revealed that diabetic risk is correlated with polymorphisms in SOD1 and SOD2 genes [36][37][38].…”