DJ-1 Protects Human Retinal Endothelial Cells From Diabetes-Related Conditions and Prevents Ischemic Damage in Mouse...

Retinal ischemia in diabetic retinopathy (DR) is caused by the apoptosis of capillary pericytes and endothelial cells. In this study, we investigated the role of the Parkinson-associated protein DJ-1 (PARK7) in retinal capillary degeneration.

DJ-1 levels were measured in diabetic and non-diabetic human retinas by immunostaining and Western blotting. Human retinal endothelial cells (HRECs) were cultured in high glucose or with a cytokine mixture (CM). The effect of inhibition of DJ-1 in HREC with isatin on Nε-carboxymethyl lysine (CML), inducible nitric oxide synthase (iNOS), nuclear factor erythroid 2-related factor (Nrf2), nuclear factor kappa (NF-κB), and cleaved caspase-3 was investigated. AAV2-PARK7, driven by the endothelial cell-specific Tie2 promoter, was intravitreally injected into the mouse's eyes, and the effect of the retinal transduced DJ-1 on capillaries was investigated following ischemia/reperfusion injury.

DJ-1 levels were observed to be reduced in human retinas with DR and in HREC cultured under high-glucose conditions. Isatin treatment increased the CML and iNOS levels in HREC. Treatment of HREC with CM promoted nuclear translocation of NF-κB and activation of caspase-3; co-treatment with isatin further exacerbated these effects. Isatin treatment significantly suppressed the CM-induced Nrf2 translocation in HREC. Intravitreal injection of AAV2-tie2-PARK7 resulted in high expression of DJ-1 in retinal capillaries and significantly reduced formation of acellular capillaries from ischemia/reperfusion injury.

The results suggest that DJ-1 protects retinal capillary endothelial cells from damage caused by hyperglycemia and ischemia and that enhancing DJ-1 activity could be a strategy for mitigating early retinal damage in DR.