alexa Angiotensin II type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina.
Diabetes & Endocrinology

Diabetes & Endocrinology

Endocrinology & Metabolic Syndrome

Author(s): Kurihara T, Ozawa Y, Nagai N, Shinoda K, Noda K,

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Abstract 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.
This article was published in Diabetes and referenced in Endocrinology & Metabolic Syndrome

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