Photoreceptor degeneration and retinal inflammation induced by very low-density lipoprotein receptor deficiency.
Photoreceptor degeneration and retinal inflammation induced by very low-density lipoprotein receptor deficiency.
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DOI：
10.1016/j.mvr.2009.02.005
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发表时间：
2009-06
影响因子：
3.1
通讯作者：
Ma JX
中科院分区：
文献类型：
--
作者：
Chen Y;Hu Y;Moiseyev G;Zhou KK;Chen D;Ma JX
我们以前的研究表明，极低密度脂蛋白受体（VLDLR）是Wnt通路的负调控因子。本研究表明，VLDLR基因敲除（Vldlr−/−）小鼠在早期表现出受损的视锥ERG反应。中波长视锥细胞的免疫染色显示Vldlr−/−小鼠视网膜中的视锥细胞密度显著降低，视锥细胞外节缩短。在年龄较大时，Vldlr−/−小鼠表现出杆ERG反应下降，感光细胞核层减少，视紫红质水平降低，视色素的发色团11-顺式视网膜水平降低。荧光素血管造影和渗透性测定显示，Vldlr−/−小鼠有严重的视网膜血管渗漏。紧密连接蛋白ZO-1在Vldlr−/−小鼠视网膜中下调，进一步支持血视网膜屏障受损。视网膜切片中周细胞和内皮细胞的双重染色显示，Vldlr−/−小鼠的新生血管缺乏周细胞覆盖，表明Vldlr−/−小鼠视网膜血管成熟受损。视网膜血管中粘附的白细胞染色显示Vldlr−/−小鼠中存在显著的白细胞停滞。此外，Vldlr−/−小鼠显示多种促炎因子的表达上调，并激活了炎症的关键调节因子NF-κB和HIF-1α。这些发现表明VLDLR的缺乏会导致视网膜变性和炎症。
Our previous studies have shown that very low-density lipoprotein receptor (VLDLR) is a negative regulator of the Wnt pathway. The present study showed that VLDLR gene knockout (Vldlr−/−) mice displayed impaired cone ERG responses at early ages. Immunostaining of mid-wavelength cones showed significantly decreased cone densities in the retina and shortened cone outer segments in Vldlr−/− mice. At older ages, Vldlr−/− mice displayed declined rod ERG responses, decreased layers of photoreceptor nuclei, reduced rhodopsin levels and decreased levels of 11-cis retinal, the chromophore of visual pigments. As shown by fluorescein angiography and permeability assay, Vldlr−/− mice had severe retinal vascular leakage. ZO-1, a tight junction protein, was down-regulated in Vldlr−/− mouse retinae, further supporting the impaired blood-retinal barrier. Double staining of pericytes and endothelial cells in retinal sections revealed that neovasculature in Vldlr−/− mice lacks pericyte coverage, suggesting impaired maturation of retinal vasculature in Vldlr−/− mice. Staining of adherent leukocytes in the retinal vasculature revealed significant leukostasis in Vldlr−/− mice. Moreover, Vldlr−/− mice displayed up-regulated expression of multiple pro-inflammatory factors and activated NF-κB and HIF-1α, key regulators of inflammation. These findings suggest that deficiency of VLDLR leads to retinal degeneration and inflammation.
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