Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment

Abstract

It has been postulated that the accumulation of advanced glycation end products (AGEs) in the kidney is important in the pathogenesis of diabetic nephropathy. Previously, aminoguanidine has been shown to inhibit the accumulation of renal AGEs and to retard the development of experimental diabetic nephropathy. The present study serially assessed the accumulation of AGEs in the aorta and kidney, as well as renal functional and structural parameters over 32 weeks of experimental diabetes in the absence and presence of aminoguanidine. In addition, it was determined if aminoguanidine was more effective if administered earlier or later in the evolution of diabetic nephropathy by treating diabetic rats with aminoguanidine in the first or second half of the 32-week study period. In the serial studies, glomerular and renal tubular fluorescence increased over the 32 week period and this increase was attenuated by aminoguanidine treatment. Concomitant with the effects of aminoguanidine on fluorescence, there was a retardation in the rise in urinary 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 were increased in diabetic rats as assessed by tissue fluorescence. Using a specific RIA, renal AGEs were increased in diabetic rats and decreased by aminoguanidine treatment, administered over the entire 32 weeks or in the first or latter half of the 32-week study period. Aminoguanidine therapy for the entire 32-week study period retarded the rise in albuminuria in the diabetic rats and was more effective than 16 weeks 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. Similar effects 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 time dependent and closely 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.

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

“…In fact, nephroprotective agents often reduce proteinuria and AGE accumulation at the same time. However, the specific pathogenetic role of AGEs has been established in animals fed a high vs low AGE diet [37], and pharmacologically using a specific AGE crosslink breaker or AGE inhibitors [32,38,39]. Therefore, although we cannot prove directly the causal link between reduced AGE content and proteinuria in the present study, it seems that the reduction of tissue AGEs, e.g.…”

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

“…Animals were placed in metabolic cages every 4 weeks (Iffa Credo, L'Arbesele, France) for collection of urine over 24 h for measurement of albumin concentration by radioimmunoassay as previously described [25]. Systolic blood pressure (SBP) was assessed by tail cuff plethsymography in conscious, preheated rats [26] every 4 weeks.…”

Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195

“…In relation to diabetic nephropathy, AG attenuates the rise in albuminuria and prevents mesangial expansion in diabetic rats [27,28]. Aminoguanidine has a renoprotective effect and the finding that this effect is related to the duration of therapy emphasizes its potential importance in clinical events [26].…”

“…Aminoguanidine (AG) [23], a hydrazine-like compound which blocks AGE formation by interacting with Amadori-derived products [24], has been shown to retard the development of diabetic microvascular and macrovascular complications in experimental animals [10,12,13,15,25,26]. In relation to diabetic nephropathy, AG attenuates the rise in albuminuria and prevents mesangial expansion in diabetic rats [27,28].…”