Kumar Pankaj, Nag Tapas Chandra, Jha Kumar Abhiram, Dey Sanjay Kumar, Kathpalia Poorti, Maurya Meenakshi, Gupta Chandan Lal, Bhatia Jagriti, Roy Tara Sankar, Wadhwa Shashi
Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India.
Department of Biochemistry, Delhi University South Campus, New Delhi 110021, India.
Toxicology. 2017 Dec 1;392:22-31. doi: 10.1016/j.tox.2017.10.005. Epub 2017 Oct 6.
Iron is implicated in age-related macular degeneration (AMD). The aim of this study was to see if long-term, experimental iron administration with aging modifies retinal and choroidal structures and expressions of iron handling proteins, to understand some aspects of iron homeostasis. Male Wistar rats were fed with ferrous sulphate heptahydrate (500mg/kg body weight/week, oral; elemental iron availability: 20%) from 2 months of age onward until they were 19.5 month-old. At 8, 14 and 20 months of age, they were sacrificed and serum and retinal iron levels were detected by HPLC. Oxidative stress was analyzed by TBARS method. The retinas were examined for cell death (TUNEL), histology (electron microscopy) and the expressions of transferrin, transferrin receptor-1 [TFR-1], H- and L-ferritin. In control animals, at any age, there was no difference in the serum and retinal iron levels, but the latter increased significantly in 14- and 20 month-old iron-fed rats, indicating that retinal iron accumulation proceeds with progression of aging (>14 months). The serum and retinal TBARS levels increased significantly with progression of aging in experimental but not in control rats. There was significant damage to choriocapillaris, accumulation of phagosomes in retinal pigment epithelium and increased incidence of TUNEL+ cells in outer nuclear layer and vacuolation in inner nuclear layer (INL) of 20 month-aged experimental rats, compared to those in age-matched controls. Vacuolations in INL could indicate a long-term effect of iron accumulation in the inner retina. These events paralleled the increased expression of ferritins and transferrin and a decrease in the expression of TFR-1 in iron-fed rats with aging, thereby maintaining iron homeostasis in the retina. As some of these changes mimic with those happening in eyes with AMD, this model can be utilized to understand iron-induced pathophysiological changes in AMD.
铁与年龄相关性黄斑变性（AMD）有关。本研究的目的是观察随着年龄增长长期进行实验性铁给药是否会改变视网膜和脉络膜结构以及铁处理蛋白的表达，以了解铁稳态的某些方面。从2月龄起，雄性Wistar大鼠口服七水合硫酸亚铁（500mg/kg体重/周；元素铁供应量：20%），直至19.5月龄。在8、14和20月龄时，将它们处死，通过高效液相色谱法检测血清和视网膜铁水平。采用硫代巴比妥酸反应物（TBARS）法分析氧化应激。检查视网膜的细胞死亡情况（TUNEL法）、组织学（电子显微镜）以及转铁蛋白、转铁蛋白受体-1 [TFR-1]、H型和L型铁蛋白的表达。在对照动物中，任何年龄的血清和视网膜铁水平均无差异，但在14月龄和20月龄的铁喂养大鼠中，视网膜铁水平显著升高，表明视网膜铁积累随着年龄增长（>14个月）而增加。在实验大鼠中，血清和视网膜TBARS水平随着年龄增长显著升高，而对照大鼠中则无此现象。与年龄匹配的对照大鼠相比，20月龄实验大鼠的脉络膜毛细血管有明显损伤，视网膜色素上皮中有吞噬体积累，外核层TUNEL+细胞发生率增加，内核层（INL）出现空泡化。INL中的空泡化可能表明内视网膜中铁积累的长期影响。这些事件与铁喂养大鼠随着年龄增长铁蛋白和转铁蛋白表达增加以及TFR-1表达减少相平行，从而维持视网膜中的铁稳态。由于其中一些变化与AMD眼中发生的变化相似，因此该模型可用于了解铁诱导的AMD病理生理变化。
