Response of capillary cell death to aminoguanidine predicts the development of retinopathy: Comparison of diabetes and galactosemia

PURPOSE. To examine the relationship between early retinal capillary cell a poptosis and late histologic lesions of diabetic retinopathy and to compare the effects of aminoguanidine (AMG) on the retinopathies caused by diabete s and galactose feeding. METHODS. Rats with alloxan-induced diabetes and rats fed a 30% galactose di et (known to induce diabetic-like retinopathy) were assigned randomly to re ceive diet with (2.5 g/kg diet) or without AMG. After 6 to 8 months of diab etes or galactosemia, retinal trypsin digests were prepared, and capillary cell apoptosis was quantitated using the Tdt-mediated dUTP nick-end labelin g (TUNEL) reaction in association with morphologic evidence of nuclear frag mentation. At 18 months duration, pericyte ghosts and acellular capillaries were quantitated in the isolated vasculature. Several advanced glycation e nd products (AGEs) were measured at 4 months of study and at 18 months of s tudy by established methods to assess biochemical effects of AMG. RESULTS. As expected, both diabetic and galactosemic rats showed increased frequency of TUNEL-positive capillary cells at 6 to 8 months and vascular l esions characteristic of retinopathy at 18 months. AMG inhibited both the e arly apoptosis and late histopathology in the diabetic rats, but neither of these abnormalities in the galactosemic rats. In contrast to its preventat ive effect on retinopathy in the diabetic rats, AMG showed no inhibitory ef fect on levels of hemoglobin AGE, or tail collagen pentosidine, fluorescenc e, and thermal breaking time. Diabetes of 4 months' duration did not cause a detectable increase in retinal levels of several AGES. CONCLUSIONS. The frequency of early apoptosis in retinal microvascular cell s predicted the development of the histologic lesions of retinopathy in dia betes as well as in galactosemia. The beneficial effect of AMG on retinal l esions in diabetes is exerted on pathways that are either not operative or are less important in galactosemia and that may not relate to the accumulat ion of AGEs.