Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat
Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat
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DOI：
10.1007/s00125-003-1256-8
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发表时间：
2004-01-01
期刊：
影响因子：
8.2
通讯作者：
Cooper, ME
中科院分区：
文献类型：
--
作者：
Davis, BJ;Forbes, JM;Cooper, ME
目标/假设。糖尿病肾病的进展被认为是代谢和血流动力学途径相互作用的结果。我们的目的是在糖尿病合并高血压的实验性模型中评估肾脏疾病的功能、结构、分子和细胞方面。将链脲佐菌素诱导的糖尿病自发性高血压大鼠随机分为不治疗组、血管紧张素转换酶抑制剂培哚普利(2 mg/L)、糖基化终末产物形成抑制剂(AGE)、氨基胍(1g/L)及两者联合治疗32周。糖尿病与白蛋白排泄率显著增加有关。氨基胍和培哚普利均可延缓蛋白尿的增加，但联合治疗可完全消除这一现象。两种单一疗法均可减轻肾小球硬化和肾小管间质损害，两种联合疗法均可进一步保护肾脏。与任何一种单一疗法相比，联合治疗对糖尿病所致的neparin蛋白耗竭的恢复效果也更好。原位杂交检测糖尿病大鼠TGFbeta1的表达增加，而培哚普利和氨基鸟苷可降低其表达。这些发现表明，在糖尿病相关肾损伤的情况下，阻断肾素-血管紧张素途径和晚期糖基化途径可提供更好的肾脏保护，可被视为预防和延缓进行性糖尿病肾损伤的治疗策略。
Aims/hypothesis. Diabetic renal disease has been postulated to progress as a result of an interaction between metabolic and haemodynamic pathways. Our aim was to assess the functional, structural, molecular and cellular aspects of renal disease in an experimental model of diabetes with associated hypertension.Method. Streptozotocin-induced diabetic spontaneously hypertensive rats were randomised to no treatment, the ACE inhibitor, perindopril (2 mg/l), the AGE formation inhibitor, aminoguanidine (1 g/l) and a combination of both agents and were followed for 32 weeks.Results. Diabetes was associated with a considerable increase in albumin excretion rate. Both aminoguanidine and perindopril retarded the increase in albuminuria, which was completely abrogated by combination therapy. Glomerulosclerosis and tubulointerstitial damage was reduced by both monotherapies with further renoprotection afforded by combination therapy in both cases. Combination therapy was also associated with a superior restoration in diabetes-induced nephrin protein depletion compared to either monotherapy. TGFbeta1 expression as assessed by in situ hybridisation was increased in the diabetic rats and reduced by perindopril and aminoguanidine.Conclusion/interpretation. These findings indicate that in the context of diabetes-related renal injury, blocking both the renin-angiotensin and advanced glycation pathways offers superior renoprotection and could be considered as a therapeutic strategy in the prevention and retardation of progressive-diabetic renal injury.