ArticleDiabetes2025
CD40 Induces Unfolded Protein Response, Upregulation of VEGF, and Vascular Leakage in Diabetic Retinopathy.
Article in Diabetes, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.Journal of cell communication and signaling · 2026Review
- Advances in the Role of the CD40-CD154 Pathway in the Pathogenesis of Diabetic Retinopathy.International journal of molecular sciences · 2026Review
- The Central Role of Lipid Metabolism Disorders in Diabetes Mellitus: Mechanisms, Clinical Manifestations, and Emerging Therapeutic Strategies.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Review
- Review: The role of microglia in diabetic retinopathy and its potential as a therapeutic target.Molecular vision · 2026Review
- "Age is associated with Achilles tendon thickness in older adults: an ultrasound case-control study with intra-observer reliability".Frontiers in physiology · 2026Article
- Single cell transcriptomic analysis reveals pathogenic cell heterogeneity and candidate inflammatory-associated markers in STZ-induced diabetic mouse retina.Frontiers in immunology · 2026Article
- Engineered MEVs for photoreceptor-targeted delivery of USP25 to alleviate diabetic retinopathy.Journal of nanobiotechnology · 2025Article
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Authors and funding
11 authors.
Funding
Abstract
The unfolded protein response (UPR) drives events that promote diabetic retinopathy, including vascular endothelial growth factor (VEGF) upregulation in Müller cells. How UPR is activated in vivo in the diabetic retina is not well understood. CD40 is required for development of diabetic retinopathy, but whether CD40 mediates activation of UPR sensors is unknown. CD40 ligation in Müller cells caused phospholipase Cγ1 (PLCγ1)-dependent activation of UPR sensors (PERK, IRE1α, and ATF6α) and VEGF production dependent on PLCγ1 and UPR sensors. Diabetic Cd40-/- mice did not exhibit UPR activation or VEGF upregulation in the retina. These responses were restored in diabetic Cd40-/- mice rescued to express wild-type CD40 in Müller cells but not in mice rescued to express a CD40 mutation unable to recruit TRAF2/3. Intravitreal administration of a cell-permeable CD40-TRAF2/3-disrupting peptide reduced UPR activation, VEGF upregulation, and vascular leakage in diabetic mice. CD40 and TRAF2 in Müller cells from patients with diabetic retinopathy colocalized with activated UPR sensors and VEGF. Our study indicates that CD40 (via TRAF2/3 signaling) is an inducer of UPR activation that triggers VEGF production in Müller cells. This work uncovered inhibition of CD40-TRAF2/3 signaling as a potential approach to impair UPR activation, VEGF upregulation, and vascular leakage in diabetic retinopathy. ARTICLE HIGHLIGHTS:
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