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Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

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. RESE...

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Autores principales: Kurihara, Toshihide, Ozawa, Yoko, Nagai, Norihiro, Shinoda, Kei, Noda, Kousuke, Imamura, Yutaka, Tsubota, Kazuo, Okano, Hideyuki, Oike, Yuichi, Ishida, Susumu
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2494692/
https://www.ncbi.nlm.nih.gov/pubmed/18487452
http://dx.doi.org/10.2337/db07-1281
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author Kurihara, Toshihide
Ozawa, Yoko
Nagai, Norihiro
Shinoda, Kei
Noda, Kousuke
Imamura, Yutaka
Tsubota, Kazuo
Okano, Hideyuki
Oike, Yuichi
Ishida, Susumu
author_facet Kurihara, Toshihide
Ozawa, Yoko
Nagai, Norihiro
Shinoda, Kei
Noda, Kousuke
Imamura, Yutaka
Tsubota, Kazuo
Okano, Hideyuki
Oike, Yuichi
Ishida, Susumu
author_sort Kurihara, Toshihide
collection PubMed
description 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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spelling pubmed-24946922009-08-01 Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina Kurihara, Toshihide Ozawa, Yoko Nagai, Norihiro Shinoda, Kei Noda, Kousuke Imamura, Yutaka Tsubota, Kazuo Okano, Hideyuki Oike, Yuichi Ishida, Susumu Diabetes Complications 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. American Diabetes Association 2008-08 /pmc/articles/PMC2494692/ /pubmed/18487452 http://dx.doi.org/10.2337/db07-1281 Text en Copyright © 2008, American Diabetes Association Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Complications
Kurihara, Toshihide
Ozawa, Yoko
Nagai, Norihiro
Shinoda, Kei
Noda, Kousuke
Imamura, Yutaka
Tsubota, Kazuo
Okano, Hideyuki
Oike, Yuichi
Ishida, Susumu
Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina
title Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina
title_full Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina
title_fullStr Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina
title_full_unstemmed Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina
title_short Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina
title_sort angiotensin ii type 1 receptor signaling contributes to synaptophysin degradation and neuronal dysfunction in the diabetic retina
topic Complications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2494692/
https://www.ncbi.nlm.nih.gov/pubmed/18487452
http://dx.doi.org/10.2337/db07-1281
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