The accelerated formation of advanced glycation end products (AGEs) and the overexpression of transforming growth factor beta (TGF- ) have both been implicated in the pathogenesis of diabetic microvascular and macrovascular complications. Previous studies in our laboratory have demonstrated that the vascular changes in diabetes include hypertrophy of the mesenteric vasculature. To examine the role of AGEs in this process, streptozotocin-induced diabetic rats and control animals were randomized to receive aminoguanidine, an inhibitor of AGE formation, or no treatment. Animals were studied at 7 d, 3 wk, and 8 mo after induction of diabetes. When compared with control animals, diabetes was associated with an increase in mesenteric vascular weight and an increase in media wall/lumen area. By Northern analysis, TGF- 1 gene expression was increased 100-150% ( P Ͻ 0.01) and ␣ 1 (IV) collagen gene expression was similarly elevated to 30-110% compared to controls ( P Ͻ 0.05). AGEs and extracellular matrix were present in abundance in diabetic but not in control vessels. Treatment of diabetic rats with aminoguanidine resulted in significant amelioration of the described pathological changes including overexpression of TGF- 1 and ␣ 1 (IV) collagen. These data implicate the formation of AGEs in TGF- overexpression and tissue changes which accompany the diabetic state. ( J.
It has been hypothesized that the biochemical process of advanced glycation plays an important part in the pathogenesis of diabetic vascular complications [1] and particularly in diabetic nephropathy [2]. This hypothesis was based primarily on the renoprotective effects observed with aminoguanidine (AG), an inhibitor of advanced glycation end-product formation (AGE) [3]. Aminoguanidine, however, has other actions including inhibiting nitric oxide synthase, and thus, nitric oxide production [4]. Nitric oxide has direct effects on renal haemodynamics in diabetes [5,6] and therefore it has been difficult to ascertain if the benefits of aminoguanidine relate primarily to inhibiting renal AGE accumulation.We compared the effect of AG in diabetic rats with ALT-946, N-(2-Acetamidoethyl) hydrozinecarboximidamide hydrochloride, a more potent inhibitor of AGE-derived protein modification than AG. ALT-946 is also a poor inhibitor of nitric oxide synthase with fewer toxic side effects than AG (unpublished results). We have reported previously that AG Diabetologia (2001)
AbstractAims/hypothesis. ALT-946, an inhibitor of advanced glycation with a minimal inhibitory effect on nitric oxide synthase, was compared with aminoguanidine in experimental diabetic nephropathy. Methods. In vitro and in vivo assays were used to assess the ability of ALT-946 to inhibit AGE-protein cross-link formation. Diabetic animals were randomly allocated into groups receiving aminoguanidine for 32 weeks, ALT-946 or vehicle (untreated). As a delayed intervention protocol, an additional diabetic group was treated with ALT-946 from week 16 to week 32 of the study. Non-diabetic rats were studied concurrently. Systolic blood pressure, body weight, plasma glucose, glycated haemoglobin and urinary albumin excretion were measured serially. Accumulation of advanced-glycation end products in the kidney was assessed by immunohistochemistry.Results. The ALT-946 inhibitor was more potent than aminoguanidine in inhibiting AGE-protein crosslinking both in vitro and in vivo. Increased albuminuria observed in diabetic rats was attenuated in all three treatment groups. We found no difference in body weight, blood pressure or glycaemic control with any of the treatments. The untreated diabetic group had a twofold increase in glomerular staining for advanced-glycation end products compared with the diabetic groups which received treatment. Conclusion/interpretation. ALT-946 is a potent inhibitor of advanced renal glycation end-product accumulation and reproduces the renoprotective effects of aminoguanidine. Therefore, ALT-946 should be considered as a treatment for preventing or retarding diabetic nephropathy. [Diabetologia (2001) 44: 108± 114]
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.
These findings support the hypothesis that biologically active TGF-beta plays a pathogenetic role in diabetic kidney disease and suggest that beta ig-h3 may be a useful index of TGF-beta1 bioactivity in the kidney.
The process of advanced glycation leads to irreversible cross-linking of long-lived proteins [1]. This process is accentuated in diabetes and has been postulated to contribute to the development of a range of diabetic complications including nephropathy [2], retinopathy [3] and neuropathy [4]. Aminoguanidine (AG) has previously been shown to retard the development of advanced glycation end products (AGEs) in various tissues in streptozotocin diabetes [5]. In those studies, AG was shown to decrease mesangial expansion and albuminuria, both markers of the
These results indicate that once-daily application of the testosterone topical solution 2% to the axillae is a safe and effective treatment for androgen replacement in hypogonadal men.
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