Bradykinin type 2 receptor deficiency alters vascular endothelial growth factor and atrial natriuretic peptide levels in early-stage diabetic retinopathy.

IF 4.5
Marin Radmilović, Helena Justić, Anja Barić, Martina Ratko, Iva Šimunić, Zoran Vatavuk, Aleksandra Dugandžić, Marina Dobrivojević Radmilović
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Abstract

Diabetic retinopathy is a leading cause of visual impairment among working-age adults. Given the multiple pathophysiologic functions of bradykinin and its links to vascular endothelial growth factor (VEGF) and atrial natriuretic peptide (ANP) signaling, we hypothesized their interconnected involvement in the development of retinal vascular permeability in early-stage diabetic retinopathy. Diabetic mice, bradykinin type 2 receptor (B2R) knock-out diabetic mice, and their non-diabetic controls underwent magnetic resonance imaging, fluorescein angiography, vascular permeability measurements, retinal ELISA, Western blot, qPCR, and immunohistochemistry, glycemic assessments, and evaluation of intraocular and blood pressure. Diabetes upregulated B2R expression without altering retinal bradykinin levels. B2R deficiency in diabetic mice unexpectedly exacerbated vascular permeability but ameliorated retinal thinning and ganglion cell loss. B2R-deficient animals had decreased VEGF and VEGF receptor-2 levels, despite increased gene expression, indicating a regulatory effect on protein synthesis. Both diabetes and B2R deficiency, especially the latter, increased ANP and guanylyl cyclase/natriuretic peptide receptor-A levels and their gene expression. This study provides new insights into the interplay between bradykinin, VEGF, and ANP in diabetic retinopathy. It highlights a regulatory role of B2R in VEGF and ANP signaling, suggesting targets for future research on vascular permeability and neuroprotection in early-stage diabetic retinopathy.

缓激素2型受体缺乏改变早期糖尿病视网膜病变血管内皮生长因子和心房钠肽水平。
糖尿病视网膜病变是导致工作年龄成年人视力受损的主要原因。考虑到缓激素的多种病理生理功能及其与血管内皮生长因子(VEGF)和心房利钠肽(ANP)信号的联系,我们假设它们在早期糖尿病视网膜病变视网膜血管通透性的发展中相互作用。糖尿病小鼠、慢激肽2型受体(B2R)敲除的糖尿病小鼠及其非糖尿病对照组进行了磁共振成像、荧光素血管造影、血管通透性测量、视网膜ELISA、Western blot、qPCR和免疫组织化学、血糖评估、眼内和血压评估。糖尿病上调B2R表达,但不改变视网膜缓激素水平。糖尿病小鼠的B2R缺乏出乎意料地加剧了血管通透性,但改善了视网膜变薄和神经节细胞损失。b2r缺陷动物的VEGF和VEGF受体-2水平下降,尽管基因表达增加,表明对蛋白质合成有调节作用。糖尿病和B2R缺乏,尤其是后者,均增加ANP和冠酰环化酶/利钠肽受体- a水平及其基因表达。本研究为缓激肽、VEGF和ANP在糖尿病视网膜病变中的相互作用提供了新的见解。提示B2R在VEGF和ANP信号传导中的调控作用,为未来早期糖尿病视网膜病变血管通透性和神经保护的研究提供了靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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