Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Müller cells.
Ischaemia-induced retinal neovascularisation and diabetic retinopathy in mice with conditional knockout of hypoxia-inducible factor-1 in retinal Müller cells.
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DOI：
10.1007/s00125-011-2081-0
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发表时间：
2011-06
期刊：
影响因子：
8.2
通讯作者：
Ma JX
中科院分区：
文献类型：
--
作者：
Lin M;Chen Y;Jin J;Hu Y;Zhou KK;Zhu M;Le YZ;Ge J;Johnson RS;Ma JX
已知视网膜Müller细胞产生炎性和血管生成细胞因子，其在糖尿病视网膜病变中起重要作用。缺氧诱导因子（HIF）-1已被证明在视网膜炎症和新生血管形成中起关键作用。我们试图确定Müller细胞衍生的HIF-1在氧诱导视网膜病变（OIR）和糖尿病视网膜病变中的作用，使用条件性HIF-1α（也称为HIF 1a）敲除（KO）小鼠。通过将Müller细胞中表达环化重组酶（cre，也称为P1_gp003）的小鼠与floxed Hif-1α小鼠杂交产生条件性Hif-1α KO小鼠，并用于OIR和链脲佐菌素诱导的糖尿病，以分别诱导视网膜新生血管形成和炎症。免疫印迹和免疫组化检测HIF-1α、促血管生成因子和促炎因子的表达。视网膜新生血管通过血管造影可视化，并通过计数视网膜前核进行定量。通过白细胞停滞和血管渗漏来评估视网膜炎症。虽然Hif-1α KO小鼠显示视网膜中的HIF-1α水平显著降低，但在正常条件下，它们没有表现出明显的组织学或视觉功能异常。与野生型小鼠相比，OIR的Hif-1α KO小鼠表现出血管内皮生长因子（VEGF）和细胞间粘附分子（ICAM）-1的过度产生减弱，血管渗漏减少，视网膜新生血管形成减轻。在糖尿病条件下，破坏Müller细胞中的Hif-1α可减弱视网膜血管渗漏和粘附白细胞的增加，以及VEGF和ICAM-1的过度产生。Müller细胞衍生的HIF-1α是视网膜新生血管形成、血管渗漏和炎症的关键介质，这些是糖尿病视网膜病变的主要病理变化。因此，Müller细胞衍生的HIF-1α是糖尿病视网膜病变有希望的治疗靶点。
Retinal Müller cells are known to produce inflammatory and angiogenic cytokines, which play important roles in diabetic retinopathy. Hypoxia-inducible factor (HIF)-1 has been shown to play a crucial role in retinal inflammation and neovascularisation. We sought to determine the role of Müller cell-derived HIF-1 in oxygen-induced retinopathy (OIR) and diabetic retinopathy using conditional Hif-1α (also known as Hif1a) knockout (KO) mice. Conditional Hif-1α KO mice were generated by crossing mice expressing cyclisation recombinase (cre, also known as P1_gp003) in Müller cells with floxed Hif-1α mice and used for OIR and streptozotocin-induced diabetes to induce retinal neovascularisation and inflammation, respectively. Abundance of HIF-1α and pro-angiogenic and pro-inflammatory factors was measured by immunoblotting and immunohistochemistry. Retinal neovascularisation was visualised by angiography and quantified by counting pre-retinal nuclei. Retinal inflammation was evaluated by leucostasis and vascular leakage. While the Hif-1α KO mice showed significantly decreased HIF-1α levels in the retina, they exhibited no apparent histological or visual functional abnormalities under normal conditions. Compared with wild-type counterparts, Hif-1α KO mice with OIR demonstrated attenuated overproduction of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1, reduced vascular leakage and alleviated neovascularisation in the retina. Under diabetes conditions, disruption of Hif-1α in Müller cells attenuated the increases of retinal vascular leakage and adherent leucocytes, as well as the overproduction of VEGF and ICAM-1. Müller cell-derived HIF-1α is a key mediator of retinal neovascularisation, vascular leakage and inflammation, the major pathological changes in diabetic retinopathy. Müller cell-derived HIF-1α is therefore a promising therapeutic target for diabetic retinopathy.
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