DISCORDANT EFFECTS OF GUANIDINES ON RENAL STRUCTURE AND FUNCTION AND ON REGIONAL VASCULAR DYSFUNCTION AND COLLAGEN CHANGES IN DIABETIC RATS

We examined the effects of aminoguanidine and methylguanidine on vascu lar dysfunction, glomerular structural changes, and indexes of early a nd late nonenzymatic glycation in 7-month streptozotocin-induced diabe tic rats. Kidney weight, glomerular volume, fractional mesangial volum e, glomerular capillary basement membrane width, and urinary albumin e xcretion were increased in diabetic rats. Diabetes also 1) increased v ascular albumin permeation twofold in retina, sciatic nerve, aorta, sk in, and kidney; 2) decreased renal collagenase-soluble collagen; 3) in creased collages-associated fluorescence in kidney and skin but not in aorta; and 4) increased glycated hemoglobin levels and aortic pentosi dine levels. Aminoguanidine reduced albuminuria by 70% after 4 months, and both guanidines 1) normalized aortic pentosidine levels and renal collagenase-soluble collagen, 2) had no effect on glycated hemoglobin levels or collagen-associated fluorescence (in aorta, kidney, or skin ), and 3) had little or no effect on regional albumin permeation. Thes e discordant effects of aminoguanidine on diabetes-induced vascular ch anges versus parameters of nonenzymatic glycation are consistent with a multifactorial pathogenesis of diabetic complications, including rol es for metabolic imbalances independent of nonenzymatic glycation. To the extent that glomerular matrix accumulation and increased regional albumin permeation in chronically diabetic rats are sequelae of nonenz ymatic glycation, these findings point to an important role for early glycation reactions and products.