Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice
Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice
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DOI：
10.1172/jci200111771
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发表时间：
2001-07-01
影响因子：
15.9
通讯作者：
Yamamoto, H
中科院分区：
文献类型：
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作者：
Yamamoto, Y;Kato, I;Yamamoto, H
由多种环境和遗传因素引起的血管并发症是糖尿病相关的许多残疾和预期寿命短的原因。在此，我们提供了第一个直接的体内证据，表明晚期糖基化终产物（AGEs;在长期高血糖暴露期间形成的非酶糖基化蛋白衍生物）及其受体之间的相互作用，导致糖尿病血管紊乱。魏圣美创造了在血管细胞中过度表达人类胰岛素的转基因小鼠，并将它们与另一种在出生后不久就患上胰岛素依赖型糖尿病的转基因小鼠杂交。与糖尿病对照组一样，由此产生的双转基因小鼠表现出血红蛋白A（1c）和血清AGE水平升高。双转基因小鼠表现出肾脏扩大，肾小球肥大，增加白蛋白尿，系膜扩张，先进的肾小球硬化症，并增加血清肌酐与糖尿病同窝出生的人相比，缺乏α转基因。据我们所知，这种双转基因小鼠的开发提供了第一个表现出人类肾脏变化的动物模型。此外，晚期糖尿病肾病的表型可通过给予AGE抑制剂（+/-）-2-异亚丙基亚肼基-4-氧代-噻唑烷-5-基乙酰苯胺（OPB-9195）来预防，从而确立了AGE-抑制剂系统作为克服糖尿病发病机制这一方面的有希望的靶点。
Vascular complications arising from multiple environmental and genetic factors are responsible for many of the disabilities and short life expectancy associated with diabetes mellitus, Here we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGEs; nonenzymatically glycosylated protein derivatives formed during prolonged hyperglycemic exposure) and their receptor, RAGE, lead to diabetic vascular derangement. Wie created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line that develops insulin-dependent diabetes shortly after birth. The resultant double transgenic mice exhibited increased hemoglobin A(1c) and serum AGE levels, as did the diabetic controls. The double transgenic mice demonstrated enlargement of the kidney, glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared with diabetic littermates lacking the RAGE transgene. To our knowledge, the development of this double transgenic mouse provides the first animal model that exhibits the renal changes seen in humans. Furthermore, the phenotypes of advanced diabetic nephropathy were prevented by administering an AGE inhibitor, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide(OPB-9195), thus establishing the AGE-RAGE system as a promising target for overcoming this aspect of diabetic pathogenesis.