Abstract
Abstract: :
In animal models of diabetes advanced glycation end products (AGEs) have been shown to accumulate in the retinas of diabetic animals. The inhibition of these AGEs can attenuate the formation of diabetic lesions in these models. To date very little is known about the role that AGEs play in the development of DR in humans. To further elucidate the pathophysiological effects of AGEs and their precursors on the human retina, it is important to fully characterize their presence in the retina and establish an association with the diseased state. Purpose: In this immunohistochemical study we examined the presence of an intracellularly formed methylglyoxal (MG)–AGE and the extracellularly formed AGE precursor amadori product human serum albumin (AHSA) in the retinas of 41 diabetic persons and 19 non–diabetic control subjects. Methods: A monoclonal antibody against MG–AGE and a polyclonal antibody to AHSA, were used to stain frozen retina sections which were then examined by light microscopy. Results: As expected, MG–AGE was observed as a fine diffuse granular staining pattern, that was observed to be significantly greater in diabetic retinas (P = 0.025). The staining patterns for AHSA were more vascularly associated. These patterns consisted of a fine granular staining of endothelial cells, course granules of staining within vessel walls and course granules staining just exterior to the vessel walls. When cumulatively scored the vascular associated AHSA staining was significantly higher in the diabetic retinas (P = 0.022). For type 1 diabetics this difference was even more pronounced (P = 0.004). In serial cryo–sections, a significant correlation was found between the vascular AHSA staining and the vascular staining of the apoptosis inducing FAS receptor (r = 0.667, P < 0.001). Conclusions: The increased presence of both MG–AGE and AHSA in diabetic retinas suggest that these particular glycated molecules could play a role in the development of DR in humans. The strong correlation with the apoptosis inducing FAS receptor is indicative of a more causal role for AHSA in which it could feasibly induce endothelial apoptosis through upregulation of FAS in retinal vascular endothelial cells. Further research will be needed to resolve whether their increased presence is causal or the result of the pathophysiological changes related to DR.
Keywords: diabetic retinopathy • pathology: human • cell adhesions/cell junctions