Soulis T, Cooper M E, Vranes D, Bucala R, Jerums G
Department of Medicine, Austin and Repatriation Medical Centre (Repatriation Campus), West Heidelberg, Australia.
Kidney Int. 1996 Aug;50(2):627-34. doi: 10.1038/ki.1996.358.
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.
据推测，肾脏中晚期糖基化终末产物（AGEs）的积累在糖尿病肾病的发病机制中起重要作用。此前，已证明氨基胍可抑制肾脏中AGEs的积累，并延缓实验性糖尿病肾病的发展。本研究连续评估了在实验性糖尿病32周期间，在不存在和存在氨基胍的情况下，主动脉和肾脏中AGEs的积累情况，以及肾脏功能和结构参数。此外，通过在32周研究期的前半段或后半段用氨基胍治疗糖尿病大鼠，确定了氨基胍在糖尿病肾病发展的早期或晚期给药是否更有效。在系列研究中，肾小球和肾小管荧光在32周期间增加，而这种增加被氨基胍治疗所减弱。与氨基胍对荧光的影响相伴的是，尿白蛋白排泄量的上升受到抑制，系膜扩张得到预防。糖尿病大鼠早期或晚期给予氨基胍均可降低肾小球和肾小管中的组织荧光。在32周时，通过组织荧光评估，糖尿病大鼠肾脏中的AGEs增加。使用特异性放射免疫分析（RIA），糖尿病大鼠肾脏中的AGEs增加，而在整个32周期间或32周研究期的前半段或后半段给予氨基胍治疗后，AGEs减少。在整个32周研究期内进行氨基胍治疗可延缓糖尿病大鼠蛋白尿的上升，且比在研究的前半段或后半段进行16周治疗更有效。早期和晚期给予氨基胍在延缓糖尿病大鼠蛋白尿发展的能力方面相似。在系膜扩张方面也观察到类似的效果。糖尿病大鼠肾小球基底膜厚度增加不受氨基胍影响，无论治疗持续时间或时间如何。本研究证实，肾脏中AGEs的体内生成具有时间依赖性，且与实验性糖尿病肾病的发展密切相关。氨基胍在糖尿病中的肾脏保护作用似乎与治疗持续时间有关，而与治疗时间无关。
