Glial Cell–Derived Cytokines Attenuate the Breakdown of Vascular Integrity in Diabetic Retinopathy

Abstract

The blood-retinal barrier (BRB) is a biological unit comprised of specialized capillary endothelial cells firmly connected by intercellular tight junctions and endotheliumsurrounding 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)␣ 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␣-driven trans-acting coactivator to the 5-flanking region of the gene promoter. Conversely, RAR␣ 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 RAR␣ is sufficient for significant reductions of vascular leakage in the diabetic retina, suggesting that RAR␣ 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. Diabetes

Local and Systemic Vegf-А Production in Complicated Proliferative Diabetic Retinopathy

“…Повышение содержа-ния VEGF-А во влаге передней камеры и СТ об-наруживались у пациентов с различными стадия-ми ДР. Более высокие уровни фактора роста в СТ определялись в случаях макулярного отека [23,24]. Максимальная концентрация VEGF-А отме-чались у пациентов с вторичной неоваскулярной глаукомой [25].…”

“…Показано, что содержание ростового фактора во внутриглазных средах отражает тяжесть про-лиферативного процесса в глазу и не коррелиру-ет с его концентрацией в плазме крови [24,26]. Согласно исследованию Shinoda K. и соавторов, концентрация VEGF-А во влаге передней ка-меры пациентов с ПДР не зависела от типа СД, длительности заболевания, способа контроля гликемии, уровня гликированного гемоглоби-на (HbA1c), наличия артериальной гипертензии или нефропатии [27].…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…line-derived neurotrophic factor (GDNF; Nishikiori et al, 2007a;Thang et al, 2000), which is a differentiation factor in the retina (Thang et al, 2000;Wu et al, 2004a). RA inhibits the apoptosis; a marked decrease in apoptotic cell number could be observed during the development of DR after treatment with RA (Nishikiori et al, 2008).…”

“…A possible protective mechanism might be that RA protects retinal cells by inducing GDNF production in glial cells in the retina (Nishikiori et al, 2007a,b). RAs are promising drugs for diabetic ophthalmic disease because they have anticataractogenic effects for diabetic cataracts (Nishikiori et al, 2007b), BRB-protective effects for vascular integrity (Miyajima et al, 2005;Nishikiori et al, 2007a), and neuroprotective effects against apoptosis in DR (Nishikiori et al, 2008). …”

Tamibarotene: A Candidate Retinoid Drug for Alzheimer’s Disease

“…The accumulation of Aβ on cerebral blood vessels, known as cerebral amyloid angiopathy (CAA), is a feature of aging and AD. 59) Am580 60) and Am80 (Nishikiori and Osanai, unpublished) enhanced expression of glial cell line-derived neurotrophic factor (GDNF), but decreased expression of vascular endothelial growth factor (VEGF)/vascular permeability factor in glial cells of the blood-retinal barrier (BRB) in diabetic patients. These actions normalize the excessive vascular permeability of BRB by modulating expression of tight junction proteins in capillary endothelium.…”