Oxidant stress is increased within the glomerulus in experimental diabeticnephropathy

The mechanisms by which the metabolic consequences of hyperglycaemia induce diabetic renal injury remain ill-defined. We hypothesized that oxidant str ess, a consequence of hyperglycaemia, is increased in glomeruli from Lewis rats with streptozotocin (STZ)-induced diabetes prior to major structural a nd functional glomerular damage. After 12 weeks of diabetes, Lewis rats had not developed proteinuria and their glomeruli appeared normal by light mic roscopy. However, kidneys of diabetic animals had higher levels of lipid pe roxides and malondialdehyde (MDA) than control rats. Immunohistochemistry d emonstrated MDA-lysine adducts in glomeruli of diabetic rats, and that lipi d peroxides and MDA were increased in glomerular lysates of diabetic rats. A possible mechanism for this finding was suggested by the observation that freshly isolated whole glomeruli from STZ rats showed a greater capacity t han glomeruli from control rats to produce H2O2. Activity of the inducible form of superoxide dismutase (SOD) Mn-SOD was increased in glomerular lysat es from STZ rats, consistent with its induction by oxidant stress. Immunost aining for Cu,Zn SOD showed increased protein in glomeruli, although compar ed with the increase in Mn-SOD activity, Cu,Zn-SOD activity was not substan tially increased, potentially as a result of partial inactivation of this e nzyme by glycation. The increased oxidant stress in untreated diabetic rats was a consequence of hyperglycaemia and not due to a direct nephrotoxic ef fect of STZ, as at least some of these changes were attenuated by insulin t reatment of diabetic animals. Collectively, these results demonstrate that experimental diabetes mellitus is accompanied by increased oxidant stress w ithin glomeruli.