EFFECTS OF AMINOGUANIDINE IN PREVENTING EXPERIMENTAL DIABETIC NEPHROPATHY ARE RELATED TO THE DURATION OF TREATMENT

It has been postulated that the accumulation of advanced glycation end products (AGEs) in the kidney is important in the pathogenesis of dia betic nephropathy. Previously, aminoguanidine has been shown to inhibi t the accumulation of renal AGEs and to retard the development of expe rimental diabetic nephropathy. The present study serially assessed the accumulation of AGEs in the aorta and kidney, as well as renal functi onal and structural parameters over 32 weeks of experimental diabetes in the absence and presence of aminoguanidine. In addition, it was det ermined if aminoguanidine was more effective if administered earlier o r later in the evolution of diabetic nephropathy by treating diabetic rats with aminoguanidine in the first or second half of the 32-week st udy period. In the serial studies, glomerular and renal tubular fluore scence increased over the 32 week period and this increase was attenua ted by aminoguanidine treatment. Concomitant with the effects of amino guanidine on fluorescence, there was a retardation in the rise in urin ary albumin excretion and prevention of mesangial expansion. Early or late administration of aminoguanidine in diabetic rats reduced tissue fluorescence in glomeruli and renal tubules. At 32 weeks, renal AGEs w ere increased in diabetic rats as assessed by tissue fluorescence. Usi ng a specific RIA, renal AGEs were increased in diabetic rats and decr eased by aminoguanidine treatment, administered over the entire 32 wee ks or in the first or latter half of the 32-week study period. Aminogu anidine therapy for the entire 32-week study period retarded the rise in albuminuria in the diabetic rats and was more effective than 16 wee ks of treatment either in the first or second half of the study. Early and late aminoguanidine administration were similar in their capacity to retard the development of albuminuria in diabetic rats. Similiar e ffects were observed on mesangial expansion. The increased glomerular basement thickness in diabetic rats was not affected by aminoguanidine , irrespective of duration or timing, of therapy. This study confirms that in vivo generation of AGEs in the kidney is rime dependent and cl osely linked to the development of experimental diabetic nephropathy. The renoprotective effects of aminoguanidine in diabetes appear to be related to the duration but not to the timing of treatment.