THE RELATIVE ROLES OF ADVANCED GLYCATION, OXIDATION AND ALDOSE REDUCTASE INHIBITION IN THE DEVELOPMENT OF EXPERIMENTAL DIABETIC NEPHROPATHYIN THE SPRAGUE-DAWLEY RAT

Advanced glycation is an important pathogenic mechanism in the develop ment of diabetic complications. However, other biochemical processes, such as the polyol pathway or lipid and protein oxidation which can in teract with advanced glycation can also yield tissue fluorescence and may also be implicated in the genesis of diabetic microangiopathy. Ami noguanidine is an inhibitor of advanced glycation, but it is not known if all of its effects are mediated by this mechanism. The present stu dy explores the relative contributions of aldose reductase, oxidative stress and advanced glycation on the development of aortic and renal f luorescence and urinary albumin excretion in streptozotocin diabetic r ats. The study groups included non-diabetic (control), streptozotocin diabetic rats and diabetic rats receiving aminoguanidine, the anti-oxi dants butylated hydroxytoluene and probucol and the aldose reductase i nhibitor, ponalrestat. Serial measurements of glycaemic control and ur inary albumin excretion were performed every 8 weeks. At 32 weeks, ani mals were killed, tissues removed and collagen extracted for measureme nt of fluorescence. Diabetic rats had increased fluorescence in aorta, glomeruli and renal tubules. Aminoguanidine prevented an increase in fluorescence at all three sites suggesting that diabetes-related tissu e fluorescence is predominantly due to advanced glycation. Ponalrestat retarded fluorescence in aorta only and butylated hydroxytoluene atte nuated fluorescence at the renal sites but not in the aorta. Diabetic rats had increased renal cortical sorbitol levels. Ponalrestat normali zed renal cortical sorbitol levels but aminoguanidine did not affect t his parameter. The only agent to decrease plasma thiobarbituric acid r eactive substances was butylated hydroxytoluene. Diabetic rats develop ed albuminuria over the 32-week period. This increase in urinary album in excretion was only attenuated significantly by aminoguanidine thera py, but not by probucol or ponalrestat. The effects of butylated hydro xytoluene on albuminuria were intermediate between aminoguanidine-trea ted and untreated diabetic rats. The failure of either antioxidants or aldose reductase inhibition to reproduce the renal effects of aminogu anidine suggest that aminoguanidine may act predominantly via inhibiti on of advanced glycation and not via the alternative biochemical proce sses evaluated in this study.