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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3101

Title: Human retinal pigment epithelial cell proliferation by the combined stimulation of hydroquinone and advanced glycation end-products via up-regulation of VEGF gene.
Other Titles: ヒト網膜色素上皮はヒドロキノンと最終糖化産物の共刺激により、VEGF遺伝子の発現上昇を伴って増殖する
Authors: Tsujinaka, Hiroki
Itaya-Hironaka, Asako
Yamauchi, Akiyo
Sakuramoto-Tsuchida, Sumiyo
Ota, Hiroyo
Takeda, Maiko
Fujimura, Takanori
Takasawa, Shin
Ogata, Nahoko
Keywords: Age-related macular degeneration
Advanced glycation endproduct(s)
Hydroquinone
Retinal pigment epithelial cells
Vascular endothelial growth factor
Issue Date: Jul-2015
Publisher: Elsevier
Citation: Biochemistry and biophysics reports Vol.2 p.123-131(2015 Jul)
Abstract: Although recent research showed that advanced glycation endproduct (AGE) and hydroquinone (HQ) are related to the pathogenesis of age-related macular degeneration (AMD), the mechanism how AGE and HQ induce or accelerate AMD remains elusive. In the present study, we examined the effects of AGE and HQ on changes of human retinal pigment epithelial (RPE) cell numbers and found that the viable cell numbers were markedly reduced by HQ by apoptosis and that AGE prevented the decreases of HQ-treated cell numbers by increased replicative DNA synthesis of RPE cells without changing apoptosis. Real-time RT-PCR revealed that vascular endothelial growth factor (VEGF)-A mRNA was increased by HQ treatment and the addition of HQ+AGE resulted in a further increment. The increase of VEGF secretion was confirmed by ELISA, and inhibition of VEGF signaling by chemical inhibitors and small interfering RNA decreased the HQ+AGE-induced increases in RPE cell numbers. The deletion analysis demonstrated that −102 to −43 region was essential for the VEGF-A promoter activation. Site-directed mutaions of specificity protein 1 (SP1) binding sequences in the VEGF-A promoter and RNA interference of SP1 revealed that SP1 is an essential transcription factor for VEGF-A expression. These results indicate that HQ induces RPE cell apoptosis, leading to dry AMD, and suggest that AGE stimulation in addition to HQ enhances VEGF-A transcription via the AGE-receptor for AGE pathway in HQ-damaged cells. As a result, the secreted VEGF acts as an autocrine/paracrine growth factor for RPE and/or adjacent vascular cells, causing wet AMD.
Description: 博士(医学)・甲第640号・平成27年11月27日
Copyright © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
URI: http://hdl.handle.net/10564/3101
ISSN: 24055808
Academic Degrees and number: 24601A640
Degree-granting date: 2015-11-27
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2015年度

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