Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase C.
Hyperglycemia, a well recognized pathogenetic factor of long-term complications in diabetes mellitus, not only generates more reactive oxygen species but also attenuates antioxidative mechanisms through glycation of the scavenging enzymes. Therefore, oxidative stress has been considered to be a common pathogenetic factor of the diabetic complications including nephropathy. A causal relationship between oxidative stress and diabetic nephropathy has been established by observations that (1) lipid peroxides and 8-hydroxydeoxyguanosine, indices of oxidative tissue injury, were increased in the kidneys 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-beta1 and fibronectin which are the genes implicated in diabetic glomerular injury, and (4) inhibition of oxidative stress ameliorates all the manifestations associated with diabetic nephropathy. Proposed mechanisms involved in oxidative stress associated with hyperglycemia are glucose autooxidation, the formation of advanced glycosylation end products, and metabolic stress resulting from hyperglycemia. Since the inhibition of protein kinase C (PKC) effectively blocks not only phorbol ester-induced but also high glucose- and H2O2-induced fibronectin production, the activation of PKC under diabetic conditions may also have a modulatory role in oxidative stress-induced renal injury in diabetes mellitus.
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Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea. hha4453@yumc.yonsei.ac.kr
Kim
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KH
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000503:physiopathology; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D011493:Protein Kinase C