Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase C

Hyperglycemia, a well recognized pathogenetic factor of long-term complicat ions in diabetes mellitus, not only generates more reactive oxygen species but also attenuates antioxidative mechanisms through glycation of the scave nging enzymes. Therefore, oxidative stress has been considered to be a comm on pathogenetic factor of the diabetic complications including nephropathy. A causal relationship between oxidative stress and diabetic nephropathy ha s been established by observations that (1) lipid peroxides and 8-hydroxyde oxyguanosine, indices of oxidative tissue injury, were increased in the kid neys of diabetic rats with albuminuria; (2) high glucose directly increases oxidative stress in glomerular mesangial cells, a target cell of diabetic nephropathy; (3) oxidative stress induces mRNA expression of TGF-beta 1 and fibronectin which are the genes implicated in diabetic glomerular injury, and (4) inhibition of oxidative stress ameliorates all the manifestations a ssociated with diabetic nephropathy. Proposed mechanisms involved in oxidat ive stress associated with hyperglycemia are glucose autooxidation, the for mation of advanced glycosylation end products, and metabolic stress resulti ng from hyperglycemia. Since the inhibition of protein kinase C (PKC) effec tively blocks not only phorbol ester-induced but also high glucose- and H2O 2-induced fibronectin production, the activation of PKC under diabetic cond itions may also have a modulatory role in oxidative stress-induced renal in jury in diabetes mellitus. (C) 1999 Elsevier Science Ireland Ltd. All right s reserved.