Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina.
Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina.
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作者：
Kurihara T;Ozawa Y;Nagai N;Shinoda K;Noda K;Imamura Y;Tsubota K;Okano H;Oike Y;Ishida S
目的：糖尿病所致视网膜功能障碍的发病机制尚不完全清楚。本研究的目的是显示肾素血管紧张素系统（RAS）与突触囊泡蛋白突触素和神经元活性在糖尿病视网膜的关系。研究设计与方法：采用血管紧张素II型1受体（AT1R）阻滞剂替利姆沙坦或缬沙坦治疗c57bl /6型糖尿病小鼠，采用视网膜电图分析其视网膜功能。通过免疫印迹检测视网膜RAS成分的产生和ERK（细胞外信号调节激酶）的磷酸化。采用定量RT-PCR和免疫印迹法分别检测视网膜synaptophysin mRNA和蛋白水平。在体外，通过血管紧张素ii刺激PC12D神经元细胞，在ERK信号或泛素-蛋白酶体系统（UPS）抑制或不抑制的情况下，也评估了synaptophysin水平。结果：糖尿病诱导视网膜血管紧张素II和AT1R的生成显著增加，AT1R下游的ERK活化也显著增加。AT1R阻断显著逆转糖尿病视网膜中视网膜电图变化和突触体素蛋白减少，但不影响mRNA水平。与体内AT1R介导的synaptophysin转录后下调一致，在体外将血管紧张素II应用于PC12D神经元细胞，通过AT1R引起ups介导的synaptophysin蛋白降解，这被证明是由ERK激活诱导的。结论：这些数据首次提供了ras诱导的糖尿病视网膜突触素降解和神经元功能障碍的分子证据，提示AT1R阻断可能作为糖尿病视网膜病变的一种新的神经保护治疗方法。
OBJECTIVE—Pathogenic mechanisms underlying diabetes-induced retinal dysfunction are not fully understood. The aim of the present study was to show the relationship of the renin-angiotensin system (RAS) with the synaptic vesicle protein synaptophysin and neuronal activity in the diabetic retina. RESEARCH DESIGN AND METHODS—C57BL/6 mice with streptozotocin-induced diabetes were treated with the angiotensin II type 1 receptor (AT1R) blocker telimsartan or valsartan, and retinal function was analyzed by electroretinography. Retinal production of the RAS components and phosphorylation of ERK (extracellular-signal regulated kinase) were examined by immunoblotting. Retinal mRNA and protein levels of synaptophysin were measured by quantitative RT-PCR and immunoblot analyses, respectively. In vitro, synaptophysin levels were also evaluated using angiotensin II–stimulated PC12D neuronal cells cultured with or without the inhibition of ERK signaling or the ubiquitin-proteasome system (UPS). RESULTS—Induction of diabetes led to a significant increase in retinal production of angiotensin II and AT1R together with ERK activation in the downstream of AT1R. AT1R blockade significantly reversed diabetes-induced electroretinography changes and reduction of synaptophysin protein, but not mRNA, levels in the diabetic retina. In agreement with the AT1R-mediated posttranscriptional downregulation of synaptophysin in vivo, in vitro application of angiotensin II to PC12D neuronal cells caused the UPS–mediated degradation of synaptophysin protein via AT1R, which proved to be induced by ERK activation. CONCLUSIONS—These data indicate the first molecular evidence of the RAS-induced synaptophysin degradation and neuronal dysfunction in the diabetic retina, suggesting the possibility of the AT1R blockade as a novel neuroprotective treatment for diabetic retinopathy.
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影响因子：
15.9
作者：
Barber, AJ;Lieth, E;Gardner, TW
通讯作者：
Gardner, TW
影响因子：
4.4
作者：
Sakai, T;Calderone, JB;Jacobs, GH
通讯作者：
Jacobs, GH
DOI：
10.1073/pnas.91.24.11689
发表时间：
1994-11-22
影响因子：
11.1
作者：
CARTHEW, RW;NEUFELD, TP;RUBIN, GM
通讯作者：
RUBIN, GM
影响因子：
4.4
作者：
Feit-Leichman, RA;Kinouchi, R;Chen, DF
通讯作者：
Chen, DF
影响因子：
4.1
作者：
Funatsu, H;Yamashita, H;Ori, SH
通讯作者：
Ori, SH