The Transcription Factor Islet-1 Regulates Diabetes-Induced Inner Blood-Retinal Barrier Disruption.

Purpose: The transcription factor Islet-1 (Insulin gene enhancer protein Isl-1) has been implicated in diabetic retinal neovascularization, but its role in inner blood-retinal barrier (iBRB) dysfunction in diabetic retinopathy remains unclear. This study aimed to elucidate the mechanisms by which Islet-1 drives iBRB disruption under diabetic conditions by integrating analyses of clinical samples from patients with diabetic retinopathy, in vivo studies in diabetic mouse models, and in vitro experiments using hyperglycemia-exposed human retinal microvascular endothelial cells.

Methods: The expression profile of Islet-1 in diabetic patients and experimental diabetic models were investigated by immunofluorescence staining, Western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR). Through the modulation of Islet-1 expression, we evaluated its impact on iBRB integrity under diabetic conditions and explored the molecular pathways involved in iBRB disruption.

Results: Our findings demonstrated that elevated Islet-1 expression correlates with the progression of diabetic retinopathy and the breakdown of the iBRB. Mechanistically, Islet-1 upregulation led to increased vascular endothelial growth factor A (VEGFA) expression and decreased levels of key tight junction proteins Occludin and Zonula occludens-1 (ZO-1) in retinal vascular endothelial cells.

Conclusions: Our results establish Islet-1 as a critical regulator of iBRB disruption in diabetic retinopathy and suggest that targeting Islet-1 overexpression may represent a novel therapeutic approach to mitigate iBRB dysfunction and its associated retinal pathologies.