Gardiner T A, Anderson H R, Stitt A W
Department of Ophthalmology, Queen's University of Belfast, Northern Ireland, UK.
J Pathol. 2003 Oct;201(2):328-33. doi: 10.1002/path.1429.
The purpose of this study was to investigate the advanced glycation end-product (AGE)-inhibitory properties of aminoguanidine and to determine whether treatment in long-term diabetic rats can prevent basement membrane lesions of diabetic retinopathy. Four groups of male Wistar rats were studied: untreated diabetics injected with 45 mg/kg streptozotocin, aminoguanidine-treated diabetics, untreated controls, and aminoguanidine-treated controls. After 12 months' diabetes, the retinas from six animals were processed for electron microscopy or the retinal microvasculature was isolated using the trypsin digest technique. Stereological analysis was used to estimate quantitative ultrastructural changes in the retinal capillary-associated basement membrane. Serum AGEs were quantified by competitive AGE-ELISA, while microvascular-associated, immunoreactive AGEs were analysed on retinal trypsin digests. Aminoguanidine significantly reduced serum AGEs in the diabetic group (p < 0.001). In the retinal capillaries, there was a marked reduction in AGE immunoreactivity in the aminoguanidine-treated diabetics when compared with untreated diabetics. The surface area and absolute volume of the retinal capillary basement membrane were significantly increased in the diabetic rats when compared with non-diabetic controls (p < 0.001 and p < 0.001, respectively). Aminoguanidine treatment of diabetic rats protected against basement membrane expansion when compared with untreated diabetic counterparts. Aminoguanidine treatment prevents the development of diabetes-induced basement membrane expansion in retinal capillaries. The AGE inhibition properties of aminoguanidine suggest that AGEs play an important role in the complex pathogenesis of basement membrane thickening during diabetic retinopathy.
本研究的目的是调查氨基胍对晚期糖基化终产物（AGE）的抑制特性，并确定长期治疗糖尿病大鼠是否能预防糖尿病性视网膜病变的基底膜病变。研究了四组雄性Wistar大鼠：注射45 mg/kg链脲佐菌素的未治疗糖尿病大鼠、氨基胍治疗的糖尿病大鼠、未治疗的对照大鼠和氨基胍治疗的对照大鼠。糖尿病12个月后，对六只动物的视网膜进行电子显微镜处理，或使用胰蛋白酶消化技术分离视网膜微血管。采用体视学分析来估计视网膜毛细血管相关基底膜的定量超微结构变化。通过竞争性AGE-ELISA对血清AGEs进行定量，同时对视网膜胰蛋白酶消化物中的微血管相关免疫反应性AGEs进行分析。氨基胍显著降低了糖尿病组的血清AGEs（p < 0.001）。在视网膜毛细血管中，与未治疗的糖尿病大鼠相比，氨基胍治疗的糖尿病大鼠的AGE免疫反应性明显降低。与非糖尿病对照组相比，糖尿病大鼠视网膜毛细血管基底膜的表面积和绝对体积显著增加（分别为p < 0.001和p < 0.001）。与未治疗的糖尿病大鼠相比，氨基胍治疗糖尿病大鼠可防止基底膜扩张。氨基胍治疗可预防糖尿病诱导的视网膜毛细血管基底膜扩张。氨基胍的AGE抑制特性表明，AGEs在糖尿病性视网膜病变期间基底膜增厚的复杂发病机制中起重要作用。
