Altered expression of aquaporins 1 and 4 coincides with neurodegenerative events in retinas of spontaneously diabetic Torii rats
Altered expression of aquaporins 1 and 4 coincides with neurodegenerative events in retinas of spontaneously diabetic Torii rats
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DOI：
10.1016/j.exer.2009.09.003
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发表时间：
2010-01-01
影响因子：
3.4
通讯作者：
Nakamura, Makoto
中科院分区：
文献类型：
--
作者：
Fukuda, Masahide;Nakanishi, Yoriko;Nakamura, Makoto
越来越多的证据表明，不仅微血管病变，而且神经退行性事件也发生在患有早期糖尿病的人类和啮齿动物的视网膜中。已知不同的病理会改变水选择通道水通道蛋白（AQPs） 1和4的胶质表达量和/或位置。然而，糖尿病动物视网膜中神经胶质活化、AQP蛋白表达改变和神经元死亡之间的时间关系仍有待研究。据报道，雄性自发性糖尿病Torii （SDT）大鼠最迟在40周龄时发展为糖尿病，在50周龄或更晚时表现为增殖性糖尿病视网膜病变。本研究比较了SDT大鼠和SD大鼠视网膜神经视网膜凋亡、胶质纤维酸性蛋白（GFAP）表达以及AQPs 1和AQPs 4表达的时间变化。采用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记法和视网膜冷冻切片激活的caspase 3免疫荧光法检测细胞死亡情况。采用冷冻切片和视网膜平片的免疫组化方法检测GFAP和aqps1、aqps4的表达。SDT大鼠的糖尿病在15周左右开始发展。40周龄SDT大鼠视网膜神经节细胞层和内核层凋亡细胞明显多于年龄匹配的SD大鼠视网膜和10周龄SDT大鼠。10周时，SD大鼠和SDT大鼠的GFAP免疫反应仅限于神经纤维层，而在40周时，SDT大鼠的GFAP免疫反应跨越整个视网膜，而5D大鼠则没有。AQP1表达于外视网膜，AQP4表达于内视网膜Muller细胞和星形胶质细胞的血管周围和端足，而AQP4表达于10周时的对照SD大鼠和SDT大鼠。40周龄的SDT大鼠表现出明显的高血糖，血管周围AQPs从AQP4转变为AQP1。因此，糖尿病的发展增加了神经视网膜的凋亡，这与SDT大鼠GFAP和水选择通道AQPs 1和4的表达模式改变相一致。2009爱思唯尔有限公司版权所有。
Evidence is mounting that not only microangiopathy, but also neurodegenerative events occur in the retinas of humans and rodents with early diabetes. Diverse pathologies are known to alter the amount and/or location of glial expression of the water-selective channels aquaporins (AQPs) 1 and 4. However, the temporal relationships among glial activation, the altered expression of the AQP proteins and neuronal death in the retinas of diabetic animals remains to be investigated. Male spontaneously diabetic Torii (SDT) rats reportedly develop diabetes by 40 weeks of age at the latest and manifest proliferative diabetic retinopathy at 50 weeks or later. This study compared temporal changes in neuroretinal apoptosis, glial fibrillary acidic protein (GFAP) expression and the expression of AQPs 1 and 4 between SDT rat retinas and age-matched Sprague-Dawley (SD) rat retinas. Cell death was detected by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling on retinal flatmounts and activated caspase 3 immunofluorescence of retinal cryosections. The expression of GFAP and AQPs 1 and 4 was assessed by immunohistochemistry of cryosections and retinal flatmounts. Diabetes started to develop around 15 weeks in SDT rats. Apoptotic cells in the ganglion cell layer and the inner nuclear layer were significantly more numerous in 40-week-old SDT rat retinas than in either age-matched SD rat retinas or 10-week-old SDT rats. GFAP immunoreactivity was confined to the nerve fiber layer both in SD and SDT rats at 10 weeks, whereas it spanned the whole retina in SDT rats, but not in 5D rats, at 40 weeks. AQP1 was expressed in the outer retina, whereas AQP4 was expressed in the perivascular and end feet of Muller cells and astrocytes in the inner retina in the control SD rats and the SDT rats at 10 weeks. The perivascular AQPs shifted from AQP4 to AQP1 in 40-week-old SDT rats that exhibited marked hyperglycemia. Thus, the development of diabetes increases neuroretinal apoptosis, and this coincides with an altered expression pattern of GFAP and water-selective channels AQPs 1 and 4 in SDT rats. (C) 2009 Elsevier Ltd. All rights reserved.