activity.66 Hyperglycemic activation of PKC induces expression of VEGF in smooth muscle cells.67

PKC activation contributes to increased matrix protein accumulation via several mechanisms. PKC induces the expression of TGF-b1, fibronectin, and type IV collagen, which is mediated through the inhibition of nitric oxide production.68 PKC causes an overexpression of the fibrinolytic inhibitor PAI- 1 and activates NF-kB in endothelial and vascular smooth muscle cells.69,70 PKC regulates and activates various membrane-associated NADP(H)- dependent oxidases.

Treatment with a PKC-b-specific inhibitor reduced PKC activity in the retina and renal glomeruli of diabetic animals, reversed diabetesinduced increases in retinal mean circulation time, normalized glomerular filtration rate, and corrected urinary albumin excretion.71

1.3.4 Increased Hexosamine Pathway Flux

Excess activation of the hexosamine pathway causes changes in gene activation, which are known to lead to vascular endothelial dysfunction and other changes consistent with those seen in diabetic retinopathy. Excess intracellular glucose in the form of fructose-6-phosphate is diverted from glycolysis to provide substrates for reactions requiring UDP- N-acetylglucosamine (see Fig. 1.10). End products of these diverted reactions include proteoglycans and O-linked glycoproteins. Though the mechanism by which increased flux through the hexosamine pathway mediates hyperglycemia-induced increases in gene transcription is not certain, covalent modification of the transcription factor Sp1 by N-acet- ylglucosamine (G1cNAc) might explain the link between activation of the hexosamine pathway