Diabetic retinopathy (DR) is a major cause of irreversible vision loss driven primarily by retinal vascular damage, yet its mechanisms remain incompletely understood. Here, we identify calnexin (Canx) as a critical suppressor of pathological angiogenesis in DR. We demonstrate that hyperglycemia synergizes with TNF-α to downregulate Canx in mouse retinal microvascular endothelial cells. This loss of Canx activates Nox4, leading to hyperactivation of the Ire1α/Xbp1s branch of the unfolded protein response. Consequently, endoplasmic reticulum stress is amplified, pathological Vegfa transcription is upregulated, and the inner blood-retinal barrier is disrupted. In streptozotocin-induced diabetic mouse models, Canx deficiency exacerbated endothelial dysfunction and retinal vascular pathology. Conversely, both adalimumab treatment and adeno-associated virus–mediated Canx overexpression in vivo suppressed the Nox4/Ire1α/Xbp1s/Vegfa cascade, significantly reduced vascular leakage and acellular capillary formation, attenuated retinal thinning, and normalized endothelial cell functions (proliferation, migration, tube formation). Collectively, our findings establish Canx as a key upstream regulator of Vegfa-mediated vascular injury in DR. Our study suggests that targeting Canx, either genetically or via repurposing adalimumab, represents a source-specific strategy to halt DR progression by blocking pathological Vegfa production at its origin.
- Diabetic retinopathy (DR) remains a leading cause of blindness, with current interventions often failing to halt progression.
- In mouse retinal microvascular endothelial cells (mRMVECs), hyperglycemia/tumor necrosis factor-α suppress calnexin (Canx).
- Canx downregulation drove vascular pathology in mRMVECs via the Nox4/Ire1α/Xbp1s pathway, amplifying endoplasmic reticulum stress and pathological Vegfa production. In streptozotocin-induced diabetic mouse models, Canx overexpression or adalimumab intervention attenuated DR in vivo by blocking this cascade.
- Our findings establish Canx as a critical upstream regulator, proposing Canx-targeted strategies as source-specific therapeutics for DR.
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