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Role of manganese superoxide dismutase inactivation in the early stages of diabetic nephropathy
Author(s) -
Munusamy Shankar,
Brock Robert W,
Saba Hamida,
MacMillanCrow Lee Ann
Publication year - 2006
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.20.5.a1139-c
Subject(s) - diabetic nephropathy , medicine , endocrinology , nephropathy , kidney , streptozotocin , creatinine , diabetes mellitus , superoxide dismutase , chemistry , albumin , oxidative stress
Diabetic nephropathy is a leading cause of end‐stage renal disease. It is well known that oxidants play a pivotal role in the pathophysiology of diabetic nephropathy. We hypothesize that hyperglycemia leads to an early (< 6 weeks) inactivation of manganese superoxide dismutase (MnSOD), which in turn increases mitochondrial oxidant production and the onset of early renal damage. MnSOD is the principal antioxidant responsible for scavenging superoxide radicals formed within the mitochondria. Using male Sprague Dawley rats (200g) injected with streptozotocin (65 mg/kg; i.p.), we have observed significant MnSOD inactivation of renal homogenates (65% reduction; p <.05) within 1 week of hyperglycemia; with no change in MnSOD protein levels as compared to the control group. In addition, real‐time, in vivo intravital microscopy indicated a diminished cortical blood flow and an increased free radical generation in diabetic rat kidneys (4 week) compared to control kidneys. Renal damage was assessed using serum creatinine, urinary albumin excretion, and histological analysis. Results suggest that after 4 weeks of hyperglycemia, a moderate level of tubular dilation (2.5 fold above control) was evident in diabetic rat kidneys with little change in serum creatinine or albumin excretion. These results indicate that MnSOD inactivation precedes kidney dysfunction in this model of diabetic nephropathy. Further studies are underway to examine whether induction of MnSOD (via gene delivery or pharmacological treatments) might reduce renal damage and oxidant production in this model of diabetic nephropathy.