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  • Title: Inhibition of protein kinase C might be harmful to diabetic retinopathy.
    Author: Yamagishi S, Takeuchi M.
    Journal: Med Hypotheses; 2004; 63(1):135-7. PubMed ID: 15193366.
    Abstract:
    Selective loss of retinal pericytes is the earliest histopathological hallmark in diabetic retinopathy. Various structural and functional abnormalities in diabetic retinas are the consequent of the loss of pericytes. Therefore, elucidating the molecular mechanisms for pericyte loss and targeting this characteristics change in early diabetic retinopathy may help to slow the development and progression of sight-threatening retinopathy in diabetes. Protein kinase C (PKC) inhibition has been used in therapeutic trials intended to reduce the incidence of proliferative diabetic retinopathy. However, we speculate that it is likely to do more harm than good in diabetic retinopathy because PKC inhibition augments pro-apoptotic effects of high glucose on cultured retinal pericytes. In the DCCT-Epidemiology of Diabetes Interventions and Complications Research, the reduction in the risk of progressive retinopathy resulting from intensive therapy in patients with type 1 diabetes persisted for at least four years, despite increasing hyperglycemia. These clinical studies strongly suggest that so-called "hyperglycemic memory" causes vascular damage in diabetic retinopathy. Glucose react non-enzymatically with the amino groups of proteins to initiate a complex series of rearrangement and dehydration reactions to produce a class of irreversibly cross-linked, fluorescent moieties, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs progress at an extremely accelerated rate in diabetic retinas, and these products have been implicated in the pathogenesis of loss of pericytes in diabetic retinopathy. The nature of AGEs is most compatible with the theory of 'hyperglycemic memory' as well. We hypothesize here that PKC inhibition is likely to do harm in diabetic retinopathy, while inhibition of AGE formation might be a promising therapeutic strategy for treatment of this devastating complication.
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