The process of methylglyoxal-induced retinal capillary endothelial cell degeneration in rats
The process of methylglyoxal-induced retinal capillary endothelial cell degeneration in rats
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DOI：
10.1016/j.mvr.2022.104455
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发表时间：
2022-11-24
影响因子：
3.1
通讯作者：
Nakahara, Tsutomu
中科院分区：
文献类型：
--
作者：
Kamiya, Erika;Morita, Akane;Nakahara, Tsutomu
甲基乙二醛是一种高活性的二羰基化合物，在糖尿病患者体内增加并蓄积。甲基乙二醛形成晚期糖基化终产物（AGE），有助于糖尿病并发症的发病机制，包括糖尿病视网膜病变。最近的研究表明，甲基乙二醛诱导糖尿病视网膜病变样异常的视网膜血管。本研究旨在探讨甲基甘氨酸诱导大鼠视网膜毛细血管内皮细胞变性的过程和机制。玻璃体内注射丙酮醛后2、7和14天，在视网膜中评估血管成分（内皮细胞、周细胞和基底膜）的形态学变化。玻璃体内注射甲基乙二醛可诱导视网膜毛细血管内皮细胞变性，且呈剂量和时间依赖性。周细胞的形状和分布的变化发生在毛细血管退化的视网膜注射甲基甘氨酸的眼睛开始之前。AGEs受体拮抗剂FPS-ZM 1和基质金属蛋白酶（MMP）抑制剂GM 6001可显著减轻甲基甘氨酸诱导的毛细血管内皮细胞变性。FPS-ZM 1未能防止注射甲基甘氨酸的眼睛中周细胞的病理变化。原位酶谱分析显示，MMP活性增强的血管减少周细胞覆盖的甲基甘氨酸注射眼睛的网站。这些结果表明，玻璃体内注射甲基乙二醛诱导毛细血管内皮细胞变性开始之前，通过AGE-β-非依赖性途径的周细胞的病理变化。毛细血管内皮细胞变性是通过激活AGE-RAGE途径并通过损害视网膜周细胞功能来增加内皮细胞中的MMP活性来介导的。
Methylglyoxal, a highly reactive dicarbonyl compound, is increased and accumulated in patients with diabetic mellitus. Methylglyoxal forms advanced glycation end products (AGE), contributing to the pathogenesis of diabetic complications, including diabetic retinopathy. Recent studies have shown that methylglyoxal induces diabetic retinopathy-like abnormalities in retinal vasculature. In this study, we investigated the processes and mechanisms of methylglyoxal-induced retinal capillary endothelial cell degeneration in rats. Morphological changes in vascular components (endothelial cells, pericytes, and basement membranes) were assessed in the retinas 2, 7, and 14 days after intravitreal injection of methylglyoxal. Intravitreal methylglyoxal injection induced retinal capillary endothelial cell degeneration in a dose-and time-dependent manner. Changes in the shape and distribution of pericytes occurred before the initiation of capillary regression in the retinas of methylglyoxal-injected eyes. The receptor for AGEs (RAGEs) antagonist FPS-ZM1, and the matrix metal-loproteinase (MMP) inhibitor GM6001 significantly attenuated methylglyoxal-induced capillary endothelial cell degeneration. FPS-ZM1 failed to prevent pathological changes in pericytes in methylglyoxal-injected eyes. In situ zymography revealed that MMP activity was enhanced at sites of blood vessels with reduced pericyte coverage in methylglyoxal-injected eyes. These results suggest that intravitreal methylglyoxal injection induces pathological changes in pericytes before the initiation of capillary endothelial cell degeneration via an AGE-RAGE -independent pathway. The capillary endothelial cell degeneration is mediated by activating the AGE-RAGE pathway and increasing MMP activity in endothelial cells by impairing pericyte function in the retina.