Investigation of the mechanism of diabetic macular edema

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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