Glial cell-derived cytokines attenuate the breakdown of vascular integrity in diabetic retinopathy
Glial cell-derived cytokines attenuate the breakdown of vascular integrity in diabetic retinopathy
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DOI：
10.2337/db06-1431
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发表时间：
2007-05-01
期刊：
影响因子：
7.7
通讯作者：
Sawada, Norimasa
中科院分区：
文献类型：
--
作者：
Nishikiori, Nami;Osanai, Makoto;Sawada, Norimasa
血-视网膜屏障（blood-retinal barrier，BRB）是由细胞间紧密连接的特化毛细血管内皮细胞和内皮周围的神经胶质细胞组成的生物单位。BRB对于维持视网膜微环境和低渗透性至关重要，并且在糖尿病视网膜病变进展的早期阶段受到损害。在这里，我们证明，视黄酸受体（RAR）α刺激剂优先作用于神经胶质细胞，而不是内皮细胞，通过招募RAR α驱动的反式作用共激活因子的基因启动子的5 '侧翼区，导致胶质细胞系源性神经营养因子（GDNF）的表达增强。相反，RAR α降低血管内皮生长因子（VEGF）/血管通透性因子的表达。这些基因表达的改变在体外以旁分泌方式通过调节毛细血管内皮细胞的紧密连接功能来限制血管通透性。由RAR α介导的神经胶质细胞的表型转化足以显著减少糖尿病视网膜中的血管渗漏，表明RAR α拮抗糖尿病诱导的紧密连接完整性的丧失。这些发现揭示了胶质细胞源性细胞因子如GDNF和VEGF调节BRB功能，这意味着胶质细胞可以成为糖尿病视网膜病变的可能治疗靶点。
The blood-retinal barrier (BRB) is a biological unit comprised of specialized capillary endothelial cells firmly connected by intercellular tight junctions and endothelium-surrounding glial cells. The BRB is essential for maintaining the retinal microenvironment and low permeability and is compromised in an early phase during the progression of diabetic retinopathy. Here, we demonstrate that retinoic acid receptor (RAR)alpha stimulants preferentially act on glial cells rather than endothelial cells, resulting in the enhanced expression of glial cell line-derived neurotrophic factor (GDNF) through recruitment of the RAR alpha-driven trans-acting coactivator to the 5'-flanking region of the gene promoter. Conversely, RAR alpha decreases expression of vascular endothelial growth factor (VEGF)/vascular permeability factor. These gene expression alterations causally limit vascular permeability by modulating the tight junction function of capillary endothelium in a paracrine manner in vitro. The phenotypic transformation of glial cells mediated by RARa is sufficient for significant reductions of vascular leakage in the diabetic retina, suggesting that RARa antagonizes the loss of tight junction integrity induced by diabetes. These findings reveal that glial cell-derived cytokines such as GDNF and VEGF regulate BRB function, implying that the glial cell can be a possible therapeutic target in diabetic retinopathy.