Leptin stimulates ischemia-induced retinal neovascularization - Possible role of vascular endothelial growth factor expressed in retinal endothelial cells
Leptin stimulates ischemia-induced retinal neovascularization - Possible role of vascular endothelial growth factor expressed in retinal endothelial cells
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DOI：
10.2337/diabetes.53.9.2443
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发表时间：
2004-09-01
期刊：
影响因子：
7.7
通讯作者：
Yoshimura, N
中科院分区：
文献类型：
--
作者：
Suganami, E;Takagi, H;Yoshimura, N
糖尿病视网膜病变是发达国家成人新失明的主要原因。瘦素是一种脂肪细胞源性激素，可刺激内皮细胞增殖和血管生成。本研究旨在阐明瘦素在视网膜新生血管形成中的病理生理作用。使用早产儿视网膜病变模型，缺血诱导的视网膜新生血管的小鼠模型，我们已经证明了更明显的视网膜新生血管在17日龄过表达瘦素的转基因小鼠比年龄匹配的野生型同窝出生。在17天大的瘦素缺陷型ob/ob小鼠中，缺血诱导的视网膜新生血管明显受到抑制。蛋白质印迹分析表明，一种具有生物活性的瘦素受体亚型在小鼠视网膜内皮细胞中表达。在猪视网膜内皮细胞的原代培养物中也检测到瘦素受体表达，其中它上调血管内皮生长因子（VEGF）mRNA表达。这种效应被认为至少部分是通过激活信号转导和转录激活因子（STAT）3介导的，因为显性负性形式的STAT 3的腺病毒转染消除了瘦素诱导的视网膜内皮细胞VEGF mRNA表达上调。这项研究提供的证据表明，瘦素刺激缺血诱导的视网膜新生血管形成可能通过上调内皮VEGF，从而表明，瘦素拮抗剂可能提供一种新的治疗策略，以预防或治疗糖尿病视网膜病变。
Diabetic retinopathy is the leading cause of new blindness in adults in developed countries. Leptin, an adipocyte-derived hormone, stimulates endothelial proliferation and angiogenesis. This study was designed to elucidate the pathophysiologic role of leptin in the progression of retinal neovascularization. Using the retinopathy of prematurity model, a mouse model of ischemia-induced retinal neovascularization, we have demonstrated more pronounced retinal neovascularization in 17-day-old transgenic mice overexpressing leptin than in age-matched wild-type littermates. Ischemia-induced retinal neovascularization was markedly suppressed in 17-day-old leptin-deficient ob/ob mice. Western blot analysis revealed that a biologically active leptin receptor isoform is expressed in mouse retinal endothelial cells. Leptin receptor expression was also detected in primary cultures of porcine retinal endothelial cells, where it upregulated vascular endothelial growth factor (VEGF) mRNA expression. This effect was thought to be mediated at least partly through the activation of signal transducers and activators of transcription (STAT)3, because adenoviral transfection of the dominant-negative form of STAT3 abolished the leptin-induced upregulation of VEGF mRNA expression in retinal endothelial cells. This study provides evidence that leptin stimulates the ischemia-induced retinal neovasucularization possibly through the upregulation of endothelial VEGF, thereby suggesting that leptin antagonism may offer a novel therapeutic strategy to prevent or treat diabetic retinopathy.