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Role of superoxide‐mediated disruption of renal mitochondria in hyperglycemia‐induced renal injury in vitro and in vivo
Author(s) -
Munusamy Shankar,
Brock Robert W,
MacMillanCrow Lee Ann
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a439-a
Subject(s) - mitochondrion , superoxide , oxidative stress , medicine , diabetes mellitus , endocrinology , diabetic nephropathy , nephropathy , nitrotyrosine , streptozotocin , superoxide dismutase , chemistry , biochemistry , nitric oxide , nitric oxide synthase , enzyme
Diabetic nephropathy is a serious complication in diabetic patients. Many reports have shown that hyperglycemia‐induced mitochondrial superoxide plays as a major role in the development of diabetic complications. We hypothesize that hyperglycemia disrupts renal mitochondria, and can be prevented by increasing levels of the primary mitochondrial antioxidant, manganese superoxide dismutase (MnSOD). NRK cells (rat proximal tubule cells) exposed to hyperglycemia (25 mM glucose), showed significant hyperpolarization of mitochondria within 24 h, and an increased generation of oxidants at 48 h. Downregulation of MnSOD (using siRNA delivery) significantly aggravated these changes, whereas NRK cells overexpressing MnSOD appeared to be protected from hyperglycemia‐induced changes. In addition, within 5‐weeks of streptozotocin‐induced diabetes in rats, blue native gel electrophoresis revealed alterations in respiratory complex‐III and complex‐V in the diabetic kidneys compared to control kidneys. These rats also showed a decline in glomerular filtration rate and increased nitrotyrosine staining. In conclusion, these data strongly suggest the involvement of mitochondrial oxidative stress and the protective role of MnSOD against mitochondrial injury during diabetes. Hence, therapeutic strategies to increase MnSOD activity should prevent the development of nephropathy in diabetic patients.