[Preventive strategy for the treatment of diabetic vitreoretinopathy]

Despite considerable recent advances in vitreoretinal surgery, generally performed in more advanced stages of diabetic vitreoretinopathy (DVR), a satisfying visual acuity cannot always be achieved. Even in the early DVR stages that might be detected by routine eye exams, management of general factors, such as blood glucose concentration and blood pressure, currently constitutes the only proven preventive measures. New approaches for amelioration and treatment of DVR are needed. The Hisayama study, an ongoing prospective cohort study of cardiovascular disease and its risk factors in a community in Hisayama Town adjoining Fukuoka City, revealed that the cut-off point for diagnostic fasting glucose level is lower (116 mg/dl) than that of the current diagnostic criteria (126 mg/ dl), indicating that more rigid diagnostic criteria might reduce the incidence of DVR in the Japanese population. In early stages of DVR, leukocyte adhesion in the retinal microvasuculature substantially contributes to DVR. We investigated the involvement of the Rho/ ROCK pathway in diabetic microvasculopathy and the therapeutic potential of fasudil, a selective ROCK inhibitor, and demonstrated that the Rho/ROCK pathway plays a critical role in leukocyte adhesion in diabetic retinal microvasculature and endothelial damage. Fasudil protects the vascular endothelium at least in part by inhibiting neutrophil adhesion and reducing neutrophil-induced endothelial injury via endothelial nitric oxide. In later stages of DVR, namely proliferative diabetic retinopathy, tractional retinal detachment associated with a cicatrical contraction of proliferative membranes can cause severe vision loss. We demonstrated the possible involvement of hyalocytes in proliferative membrane formation and its contraction mainly mediated through the function of TGF-beta 2 resulting in myofibroblastic transdifferentiation and phosphorylation of the myosin light chain, a downstream mediator of ROCK. ROCK inhibition by fasudil or statins successfully inhibited cicatrical contraction of the proliferative membranes both in vitro and in vivo. Further studies for direct evidence demonstrating whether altered diagnostic criteria of diabetes may lead to a lower incidence of DVR and determination of the therapeutic potential of ROCK inhibition in the clinic could provide new avenues of intervention for inhibiting DVR.