Novel transgenic mouse models develop retinal changes associated with early diabetic retinopathy similar to those observed in rats with diabetes mellitus.
Novel transgenic mouse models develop retinal changes associated with early diabetic retinopathy similar to those observed in rats with diabetes mellitus.
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DOI：
10.1016/j.exer.2013.12.009
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发表时间：
2014-02
影响因子：
3.4
通讯作者：
Kador PF
中科院分区：
文献类型：
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作者：
Guo C;Zhang Z;Zhang P;Makita J;Kawada H;Blessing K;Kador PF
糖尿病视网膜病变 (DR) 中视网膜毛细血管周细胞变性与醛糖还原酶 (AR) 活性有关。据报道，小鼠和大鼠的 DR 发展存在差异，并且这可能与视网膜山梨醇水平的差异有关，因此我们建立了新的早发性糖尿病小鼠模型，作为研究 AR 在 DR 中的作用的工具。通过将糖尿病 C57BL/6-Ins2Akita/J (AK) 与在含有平滑肌肌动蛋白-α (SMAA) 的血管组织中表达绿色荧光蛋白 (GFP)、人醛糖还原酶 (hAR) 或两者的转基因 C57BL 小鼠杂交，开发出转基因糖尿病小鼠模型。通过 HPLC 测定视网膜山梨醇水平的变化，同时通过蛋白质印迹研究生长因子和信号传导的变化。在弹性蛋白酶消化平板上定量分析视网膜血管变化。结果表明，与 AK-SMAA-GFP 小鼠相比，糖尿病 AK-SMAA-GFP-hAR 小鼠神经视网膜中的山梨醇水平较高。 AK-SMAA-GFP-hAR 小鼠表现出视网膜生长因子 VEGF、IGF-1、bFGF 和 TGFβ 的诱导，以及 P-Akt、P-SAPK/JNK 和 P-44/42 MAPK 的信号变化。 18 周龄 AK-SMAA-GFP-hAR 小鼠中单位毛细血管长度的细胞核损失增加，无细胞毛细血管的百分比显着增加。这些变化与链脲佐菌素诱导的糖尿病大鼠中观察到的变化相似。抑制 AR 可以防止小鼠和大鼠的视网膜变化。这些研究证实，小鼠中 AR 表达的增加会导致与 DR 早期相关的视网膜变化，这与在大鼠中观察到的情况类似。
Retinal capillary pericyte degeneration has been linked to aldose reductase (AR) activity in diabetic retinopathy (DR). Since the development of DR in mice and rats has been reported to differ and that this may be linked to differences in retinal sorbitol levels, we have established new murine models of early onset diabetes mellitus as tools for investigating the role of AR in DR. Transgenic diabetic mouse models were developed by crossbreeding diabetic C57BL/6-Ins2Akita/J (AK) with transgenic C57BL mice expressing green fluorescent protein (GFP), human aldose reductase (hAR) or both in vascular tissues containing smooth muscle actin-α (SMAA). Changes in retinal sorbitol levels were determined by HPLC while changes of growth factors and signaling were investigated by Western Blots. Retinal vascular changes were quantitatively analyzed on elastase-digestion flat mounts. Results show that sorbitol levels were higher in neural retinas of diabetic AK-SMAA-GFP-hAR compared to AK-SMAA-GFP mice. AK-SMAA-GFP-hAR mice showed induction of the retinal growth factors VEGF, IGF-1, bFGF and TGFβ, as well as signaling changes in P-Akt, P-SAPK/JNK, and P-44/42 MAPK. Increased loss of nuclei per capillary length and a significant increase in the percentage of acellular capillaries presented in 18 week old AK-SMAA-GFP-hAR mice. These changes are similar to those observed in streptozotocin-induced diabetic rats. Retinal changes in both mice and rats were prevented by inhibition of AR. These studies confirm that the increased expression of AR in mice results in the development of retinal changes associated with the early stages of DR that are similar to those observed in rats.