The Mechanism of TNF-α Combined With High Glucose in Regulating Calnexin Aggravates Endoplasmic Reticulum Stress in Endothelial Cell Injury of Diabetic Retinopathy.

Authors

Yaru Hou, Tianran Chen, Jiaxing Zhou, Zirui Guo, Yunnan Zhang, Jing Zhu, Yan Cui

Published in

Diabetes. Volume 75. Issue 7. Pages 1150-1161. Jul 01, 2026.

Abstract

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.

PMID:
42330304
Bibliographic data and abstract were imported from PubMed on 23 Jun 2026.

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