Abstract
Diabetic retinopathy (DR) develops in a significant proportion of patients with chronic diabetes, characterized by retinal macular edema and abnormal retinal vessel outgrowth leading to vision loss. Chrysin, a naturally-occurring flavonoid found in herb and honeycomb, has anti-inflammatory, antioxidant, and anti-cancer properties. This study sought to determine the protective effects of chrysin on retinal neovascularization with abnormal vessels and blood-retinal barrier (BRB) breakdown in 33 mM glucose-exposed human retinal endothelial cells and in db/db mouse eyes. High glucose caused retinal endothelial apoptotic injury, which was inhibited by submicromolar chrysin. This compound diminished the enhanced induction of HIF-1α, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (VEGFR2) in high glucose-exposed retinal endothelial cells. Consistently, oral administration of 10 mg/kg chrysin reduced the induction of these proteins in db/db mouse eye tissues. In addition, chrysin restored the decrement of VE-cadherin and ZO-1 junction proteins and PECAM-1 in hyperglycemia-stimulated retinal endothelial cells and diabetic mouse retina, possibly maintaining tight cell-cell interactions of endothelial cells and pericytes. Anti-apoptotic chrysin reduced the up-regulation of Ang-1, Ang-2, and Tie-2 crucial to retinal capillary occlusion and BRB permeability. Furthermore, orally treating chrysin inhibited acellular capillary formation, neovascularization, and vascular leakage observed in diabetic retinas. These observations demonstrate, for the first time, that chrysin had a capability to encumber diabetes-associated retinal neovascularization with microvascular abnormalities and BRB breakdown.
Highlights
Diabetic retinopathy (DR), known as diabetic eye disease, results in microvascular retinal changes eventually leading to visual impairment or blindness [1,2]
When human retinal microvascular endothelial cells (HRMVEC) were treated with 1–20 μM chrysin, the viability was enhanced in a dose-dependent manner
This study investigated the capability of chrysin in combating diabetes-mediated retinal neovascularization and microvascular abnormalities in high glucose-exposed retinal endothelial cells and diabetic mice
Summary
Diabetic retinopathy (DR), known as diabetic eye disease, results in microvascular retinal changes eventually leading to visual impairment or blindness [1,2]. Hyperglycemia evokes intramural pericyte apoptosis and basement membrane thickening, causing the dysfunction of blood-retinal barrier (BRB) and makes retinal vessels leaky [3,4,5]. Diabetic macular edema and blurry vision occur when the damaged vessels leak blood, fluid exudates, and lipids into the macula and retina [6,7]. Hyperglycemia-associated retinal neovascularization forming abnormal new blood vessels can accompany retinal and vitreous morphological changes [6,8]. Aberrant angiogenesis of retinal vessels that are often immature results in vitreous hemorrhage, increased vascular permeability, fibrovascular tissue formation, and traction retinal detachments leading to vision loss [9]. An ocular manifestation of diabetes, occurs owing to narrowing or blocked retinal blood
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