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IOP-induced blood-retinal barrier compromise contributes to RGC death in glaucoma

ABSTRACT: The integrity of the blood-retinal barrier (BRB) has been largely unexplored in glaucoma. We reveal that elevated intraocular pressure (IOP) partially compromises the BRB in two human-relevant inherited mouse models of glaucoma (DBA/2J and Lmx1bV265D). Experimentally increasing IOP in mouse eyes further confirms this. Notably, the compromise induces subtle leakage, happening without bleeding or detected endothelial cell junction disruption, and it precedes neurodegeneration. Leakage occurs from peripheral veins in the retinal ganglion cell layer with a concomitant loss of the transcytosis inhibitor MFSD2A. Supporting this, bulk RNA sequencing of retinal veins revealed upregulated vesicular transport and downregulated Wnt signaling in hypertensive versus control veins. Transmission electron microscopy confirmed intact tight junctions in D2 glaucoma mice, while increased vesicles suggest enhanced transcytosis. In human glaucoma eyes, albumin immunostaining showed BRB leakage in retinal veins, mirroring our mouse findings. Importantly, stabilizing β-catenin in retinal endothelial cells prevents both vascular leakage and neurodegeneration in the DBA/2J model. The occurrence of leakage in all 3 high IOP models and in human glaucoma indicates that BRB compromise may be a common, yet overlooked, mechanism in glaucoma. These findings suggest that IOP-induced BRB compromise plays a critical role in glaucoma, offering a new therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE292834 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:Purpose: The DBA/2J mouse is a model for secondary angle-closure glaucoma due to iris atrophy and pigment dispersion, which ultimately leads to increased intraocular pressure (IOP). We sought to correlate changes in retinal gene expression with glaucoma-like pathology by performing microarray analysis of retinal RNA from DBA/2J mice at 3 months before disease onset, and at 8 months, after IOP elevation. Methods: IOP was monitored monthly in DBA/2J animals by Tono-Pen and animals with normal (3 months) or elevated IOP (8 months) were identified. RNA was prepared from 3 individual retinas at each age, and the RNA was amplified and used to generate biotin-labeled probe for high density mouse Affymetrix arrays (U430.2). A subset of genes was selected for confirmation by quantitative RT-PCR using independent retina samples from DBA/2J animals at 3, 5 and 8 months of age, and compared to retinas from C57BL/6J control animals at 3 and 8 months. Results: There were changes in expression of 68 genes, with 32 genes increasing and 36 genes decreasing at 8 months versus 3 months. Upregulated genes were associated with immune response, glial activation, signaling and gene expression, while down-regulated genes included multiple crystallin genes. Significant changes in 9 upregulated genes and 2 downregulated genes were confirmed by quantitative RT-PCR, with some showing changes in expression by 5 months. Conclusions: DBA/2J retina shows evidence for glial activation and an immune-related response following IOP elevation, similar to what has been reported following acute elevation of IOP in other models. IOP was monitored monthly in DBA/2J animals by Tono-Pen and animals with normal (3 months) or elevated IOP (8 months) were identified. RNA was prepared from 3 individual retinas at each age, and the RNA was amplified and used to generate biotin-labeled probe for high density mouse Affymetrix arrays (U430.2). A subset of genes was selected for confirmation by quantitative RT-PCR using independent retina samples from DBA/2J animals at 3, 5 and 8 months of age, and compared to retinas from C57BL/6J control animals at 3 and 8 months.

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IOP-induced blood-retinal barrier compromise contributes to RGC death in glaucoma

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