Essential Role of XBP1 in Maintaining Photoreceptor Synaptic Integrity in Early Diabetic Retinopathy.
Essential Role of XBP1 in Maintaining Photoreceptor Synaptic Integrity in Early Diabetic Retinopathy.
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DOI：
10.1167/iovs.64.14.40
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发表时间：
2023-11-01
影响因子：
4.4
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中科院分区：
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糖尿病视网膜病变（DR）是导致工作年龄成人失明的主要原因，其特征在于视网膜功能障碍和神经血管变性。我们以前报道过，X-box结合蛋白1（XBP 1）的缺失导致糖尿病视网膜神经退行性变加速;然而，其机制仍然难以捉摸。本研究的目的是确定在早期DR的光感受器突触的完整性的调节中的作用的XBP 1。糖尿病诱导链脲佐菌素在视网膜特异性XBP 1条件性敲除（cKO）或野生型（WT）小鼠产生糖尿病cKO（cKO/DM）或WT/DM小鼠与非糖尿病cKO（cKO/NDM）和WT/NDM小鼠进行比较。糖尿病3个月后，通过免疫组织化学、光学相干断层扫描和视网膜电图（ERG）评估视网膜形态、结构和功能。通过共聚焦显微镜检查光感受器和双极细胞之间的突触，并使用QUANTOS算法量化突触完整性。我们发现，与所有其他组相比，cKO/DM小鼠的外核层变薄，暗适应和光适应ERG的b波振幅下降。与这些变化一致，与WT小鼠相比，cKO小鼠显示突触完整性损失增加，无论糖尿病状态如何。在寻找负责糖尿病和XBP 1缺陷型视网膜中光感受器突触完整性丧失的候选分子时，我们发现与WT/DM相比，cKO/DM视网膜中DLG 4/PSD-95的mRNA和蛋白水平降低。这些发现表明，XBP 1是维持突触完整性和视网膜功能的关键调节因子，可能通过调节突触支架蛋白。
Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults characterized by retinal dysfunction and neurovascular degeneration. We previously reported that deletion of X-box binding protein 1 (XBP1) leads to accelerated retinal neurodegeneration in diabetes; however, the mechanisms remain elusive. The goal of this study is to determine the role of XBP1 in the regulation of photoreceptor synaptic integrity in early DR. Diabetes was induced by streptozotocin in retina-specific XBP1 conditional knockout (cKO) or wild-type (WT) mice to generate diabetic cKO (cKO/DM) or WT/DM mice for comparison with nondiabetic cKO (cKO/NDM) and WT/NDM mice. Retinal morphology, structure, and function were assessed by immunohistochemistry, optical coherence tomography, and electroretinogram (ERG) after 3 months of diabetes. The synapses between photoreceptors and bipolar cells were examined by confocal microscopy, and synaptic integrity was quantified using the QUANTOS algorithm. We found a thinning of the outer nuclear layer and a decline in the b-wave amplitude in dark- and light-adapted ERG in cKO/DM mice compared to all other groups. In line with these changes, cKO mice showed increased loss of synaptic integrity compared to WT mice, regardless of diabetes status. In searching for candidate molecules responsible for the loss of photoreceptor synaptic integrity in diabetic and XBP1-deficient retinas, we found decreased mRNA and protein levels of DLG4/PSD-95 in cKO/DM retina compared to WT/DM. These findings suggest that XBP1 is a crucial regulator in maintaining synaptic integrity and retinal function, possibly through regulation of synaptic scaffold proteins.
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