Investigation of the mechanism of diabetic macular edema

糖尿病视网膜病变引起视力障碍的主要原因是基于血管高通透性的黄斑水肿和基于新生血管的增生组织。血管内皮生长因子（Vascular endothelial growth factor， VEGF= Vascular permeability factor， VPF）与糖尿病视网膜病变的发病密切相关。我们之前报道过VEGF的作用不仅与VEGF本身的量有关，还与其受体（KDR）在视网膜毛细血管内皮细胞表面的表达量有关。此外，我们报道了KDR基因的表达受到转录因子Sp1的正调控。在本研究中，我们明确了临床上用于胰岛素抵抗正常化的PPARgamma激动剂可以通过抑制Sp1与KDR启动子区域的结合来下调KDR基因的表达。这些结果表明，PPARgamma受体激动剂可能是一种治疗糖尿病视网膜病变的有希望的药物，它不仅可以使胰岛素抵抗状态正常化，还可以下调视网膜毛细血管内皮细胞上VEGF受体的表达。此外，虽然机制尚不清楚，但玻璃体对黄斑区域的分力被认为是糖尿病性黄斑水肿的发病机制之一。我们从玻璃体中分离出被认为是巨噬细胞谱系的透明细胞，并检查了其在各种情况下的功能特性。血小板衍生生长因子- bb (PDGF-BB)，已知在糖尿病眼中上调，可增强透明细胞的增殖、变色和凝胶收缩。此外，tgf - β的活性在糖尿病眼中也被上调，与PDGF相比，tgf - β强烈促进强直性和持续性凝胶收缩。我们进一步证明PDGF-BB和tgf - β引起的凝胶收缩机制主要是通过rhok激酶活性介导的。因此，我们证明，rho激酶抑制剂（羟法舒地尔），已经在临床用于小脑血管痉挛可以抑制凝胶收缩的透明质细胞。因此，我们指出了治疗糖尿病视网膜病变的新策略的可能性。少

The main causes of visual disturbance due to diabetic retinppathy are macular edema based on vascular hyperpermeability and proliferative tissue based on the neovascularization. Vascular endothelial growth factor (VEGF=vascular permeability factor;VPF) is known to be closely associated with the pathogenesis of diabetic retinopathy.We previously reported that the effect of VEGF was not only due to the amount of VEGF itself but also due to the amount of the expression of its receptor (KDR) on the surface of retinal capillary endothelial cells. Additionally, we reported that the expression of KDR gene is positively regulated by the transcription factor Sp1.In this study, we clarified that PPARgamma agonist, which is already in clinical use as to normalize the insulin resistant state, could down-regulate the expression of KDR gene through the inhibition of the binding of Sp1 to the KDR promoter region. These result indicate that the PPARgamma agonist might be a hopeful drug for the treatme … More nt of diabetic retinopathy through not only normalizdng the insulin-resistent state but also down-regulating the expression of VEGF receptor on the retinal capillary endothelial cells.In addition, while the mechanisms are still unclear, fractional force of the vitreous to the macular area is thought to be one of the pathogenesis of diabetic macular edema. We isolated hyalocytes, which are thought to be rnacrophage lineage, from the vitreous and examined its functional properties under various circumstances. Platelate-derived growth factor-BB(PDGF-BB), which is known to be up-regulated in the diabetic eyes, enhanced the proliferation, chamotaxis and gel contraction by the hyalocytes. Furthermore, TGF-beta, whose activity is also known to be up-regulated in the diabetic eyes, strongly promoted tonic and continuous gel contraction as compared with PDGF.We further demonstrated that the gel contraction mechanism due to PDGF-BB and TGF-beta is mainly mediated through rho-kinase activity. We thus demonstrated that the rho-kinase inhibitor (Hydroxyfasudil), alredy in clinical use for cerebellar vascular spasm could inhibit the gel contraction by the hyalocyte. We thus indicated the possibility of new strategy for the treatment of diabetic retinopathy. Less