MECHANISMS OF LOSS

The underlying causes and mechanisms of early pericyte dropout in diabetic retinopathy remain still unclear. It is possible that pericyte loss is a result of passive processes, such as degeneration and apoptosis. For example, STZ-diabetic Wistar rats showed a 2.65 fold increase in the numbers of TUNEL positive cells (including pericytes) in retinae after 11 months of hyperglycemia (105). Pericyte death was also present in retinal vessels of diabetic patients suggesting its relevance in clinical disease (106).

Biochemical Pathways

ALDOSE REDUCTASE

The selective damage of pericytes by chronic hyperglycemia may be explained by altered biochemical pathways which have been implicated in the pathogenesis of microvascular damage, so that pericyte loss may be the consequence of hyperglycemic toxicity. The four biochemical pathways that have been discussed over years to be involved in the pathogenesis of diabetic complications are i. increased activity of the polyolpathway, ii. activation of PKC isoforms by de novo synthesis of diacylglycerol, iii. increased flux through the hexosamine pathway and iiii. supply of glycolytic intermediates for the formation of AGEs. The first pathway to be studied in this regard was the aldose reductase pathway, as immunological evidence had suggested the selective presence of aldose reductase in pericytes (107). When glucose levels in cells are low, the enzyme aldose reductase functions by detoxifying aldehydes to inactive alcohols. When glucose levels in cells rise in diabetes, the enzyme starts to reduce glucose to sorbitol, and this process consumes the cofactor NADPH. Since NADPH is an essential cofactor for the regeneration of an important intracellular antioxidant, reduced glutathione, its depletion may induce a significant impact on cellular defense against oxidative stress. According to novel findings, the expression and the activity of aldose reductase are increased in bovine retinal pericytes in vitro when cultured in high glucose (108), and are accompanied by elevated intracellular sorbitol levels. Whether this leads to increased pericyte death and is amenable to pharmacological inhibition has not yet been demonstrated. Overall, in line with the notion that the absolute levels of aldose reductase in the retina may be too low to contribute significantly to retinopathy development, the majority of experimental, and one large clinical trial failed to establish this pathway as playing a major role.

AGE FORMATION

Chronic hyperglycemia-induced formation of reactive oxygen species and AGEs, which accumulate in pericytes in vivo (109), might be able to initiate pericyte degeneration. Injection of exogenous AGE into nondiabetic animals resulted in a selective uptake in pericytes (110). In principle, repeated injection of high doses of AGE-modified rat serum can induce selective pericyte loss in normal rats after 2 weeks (111). Moreover, endogenous AGEs can form and accumulate in pericytes (112). While the ingestions of exogenous AGEs is consistent with the propensity of phagocytosis of pericytes, the formation of endogenous AGEs in pericytes is inconsistent with the prior finding that