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.