A central role for protein kinase C overactivity in diabetic glomerulosclerosis: implications for prevention with antioxidants, fish oil, and ACE inhibitors.
The primary etiologic factor in diabetic glomerulosclerosis appears to be an overproduction of transforming growth factor-beta by mesangial cells, which in turn reflects a hyperglycemically mediated overactivation of protein kinase C (PKC) throughout the glomerulus. Membrane-active antioxidants, fish oil, and angiotensin-converting enzyme inhibitors can act to down-regulate glomerular PKC activity, via a variety of mechanisms that may include activation of diacylglycerol kinase and suppression of phosphatidate phosphohydrolase, support of endothelial nitric oxide and heparan sulfate production, inhibition of thromboxane and angiotensin synthesis/activity, and correction of glomerular hypertension. The beneficial impact of these measures on vascular endothelial function may be of more general utility in the prevention of diabetic complications such as retinopathy, neuropathy, and atherosclerosis. Adjunctive use of gamma-linolenic acid is indicated for prevention of neuropathy, and it is conceivable that bioactive chromium will have protective activity not solely attributable to improved glycemic control. Re-establishing euglycemia must clearly remain the core strategy for preventing diabetic complications, but when glycemic control remains suboptimal, practical, safe measures are at hand for decreasing risk.
McCarty
M F
MF
Nutrition 21, San Diego, CA 92109, USA.
D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D003925:Diabetic Angiopathies / Q000517:prevention & control; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D004789:Enzyme Activation; D005395:Fish Oils / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology; D007678:Kidney Glomerulus / Q000201:enzymology; D015227:Lipid Peroxidation; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D005395:Fish Oils; D006497:Heparan Sulfate; D009569:Nitric Oxide; D011493:Protein Kinase C; D013928:Thromboxane A2; D016212:Transforming Growth Factor beta