An Overview of Diabetes and Ocular Health

Nakao, Shintaro; Hata, Yoshinobu

doi:10.1016/b978-0-12-385083-6.00013-9

Cited by 4 publications

(2 citation statements)

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“…DR pathogenesis is accompanied by microvascular complications such as hyperpermeability, angiogenesis, microthrombosis, and inflammation [29, 30]. Diabetic retinal capillary disorder may be associated with retinal leukocyte stasis (leukostasis) at early nonproliferative stages of DR [31–34].…”

Section: Rock As a Therapeutic Target For Diabetic Retinopathymentioning

confidence: 99%

“…While visual acuity is not always affected in nonproliferative stages of diabetic retinopathy (DR) without DME, DR progression can cause neovascularization, vitreous hemorrhages, preretinal fibrovascular proliferation, and tractional retinal detachment, which can lead to severe vision loss [ 28 ]. DR pathogenesis is accompanied by microvascular complications such as hyperpermeability, angiogenesis, microthrombosis, and inflammation [ 29 , 30 ]. Diabetic retinal capillary disorder may be associated with retinal leukocyte stasis (leukostasis) at early nonproliferative stages of DR [ 31 – 34 ].…”

Section: Rock As a Therapeutic Target For Diabetic Retinopathymentioning

confidence: 99%

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Rho-Kinase/ROCK as a Potential Drug Target for Vitreoretinal Diseases

Yamaguchi

Nakao

Arima

et al. 2017

Journal of Ophthalmology

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Rho-associated kinase (Rho-kinase/ROCK) was originally identified as an effector protein of the G protein Rho. Its involvement in various diseases, particularly cancer and cardiovascular disease, has been elucidated, and ROCK inhibitors have already been applied clinically for cerebral vasospasm and glaucoma. Vitreoretinal diseases including diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinoapthy are still a major cause of blindness. While anti-VEGF therapy has recently been widely used for vitreoretinal disorders due to its efficacy, attention has been drawn to new unmet needs. The importance of ROCK in pathological vitreoretinal conditions has also been elucidated and is attracting attention as a potential therapeutic target. ROCK is involved in angiogenesis and hyperpermeability and also in the pathogenesis of various pathologies such as inflammation and fibrosis. It has been expected that ROCK inhibitors will become new molecular target drugs for vitreoretinal diseases. This review summarizes the recent progress on the mechanisms of action of ROCK and their applications in disease treatment.

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Section: Rock As a Therapeutic Target For Diabetic Retinopathymentioning

confidence: 99%

Section: Rock As a Therapeutic Target For Diabetic Retinopathymentioning

confidence: 99%

Rho-Kinase/ROCK as a Potential Drug Target for Vitreoretinal Diseases

Yamaguchi

Nakao

Arima

et al. 2017

Journal of Ophthalmology

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A Key Role for ROCK in TNF-α–Mediated Diabetic Microvascular Damage

Arita

Nakao

Kita

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Leukocyte adhesion releases tumor necrosis factor (TNF)-a that contributes to endothelial damage in early diabetic retinopathy (DR). Rho/Rho-kinase (ROCK) signaling mediates retinal endothelial damage in early DR. However, whether ROCK regulates TNF-a-mediated diabetic vascular damage is unknown. Here, the contribution of ROCK to TNFa-mediated microvascular damage is investigated. METHODS.In DR patients and nondiabetic control subjects, the levels of membranous (m) TNF-a on neutrophils, soluble (s) TNF-a and its receptors in sera, were measured. In cultured microvascular endothelial cells, phosphorylation of myosin phosphatase target protein (MYPT)-1, a downstream target of ROCK, was investigated with TNF-a or DR sera pretreatment. TNF-a-induced intercellular adhesion molecule-1 (ICAM-1) and endothelial nitric oxide synthase (eNOS) phosphorylation were measured with and without ROCK inhibition by fasudil or ROCK-specific small-interfering RNA (siRNA). In isolated neutrophils from control subjects, MYPT-1 phosphorylation was investigated in the presence of TNF-a. The impact of ROCK inhibition by fasudil on TNF-a-induced integrin (CD18, CD11a, CD11b) and intracellular cytoskeletal changes were investigated. RESULTS.The serum levels of mTNF-a, sTNF-a, and its receptors were significantly elevated in DR patients. TNF-a as well as DR sera promoted MYPT-1 phosphorylation in endothelial cells, which was significantly reduced by anti-TNF-a neutralizing antibody. TNF-a-induced ICAM-1 expression, eNOS dephosphorylation, cytoskeletal changes, and CD11b/18 expression in neutrophils were significantly suppressed by fasudil as well as ROCK-specific siRNA.CONCLUSIONS. ROCK is a key mediator of TNF-a signaling in diabetic microvessels. The important role of TNF-a in early DR provides a new rationale for ROCK inhibition beyond the previously shown mechanisms. (Invest Ophthalmol Vis Sci.

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