CD40 INDUCES UNFOLDED PROTEIN RESPONSE, UPREGULATION OF VEGF AND VASCULAR LEAKAGE IN DIABETIC RETINOPATHY

• DOI: 10.2337/db23-0538
• Publication Date: 2025-02-20T15:55:11Z
• Authors: Sarah Vos; Jose-Andres C. Po...; Alyssa Hubal; Reena Bapputty; Amelia Pfaff; Rachel Aaron; Matthew Weng; Da Sun; Zheng-Rong Lu; Jin-Sang Yu; Carlos S. Subauste

The unfolded protein response (UPR) drives events that promote diabetic retinopathy including VEGF upregulation in Müller cells. How UPR is activated vivo the retina not well understood. CD40 required for development of but whether mediates activation sensors unknown. ligation cells caused phospholipase Cγ1 (PLCγ1)-dependent (PERK, IRE1α and ATF6α), production dependent on PLCγ1 sensors. Diabetic Cd40-/- mice did exhibit retina. These responses were restored rescued to express WT a mutant unable recruit TRAF2,3. Intravitreal administration cell-permeable CD40-TRAF2,3 disrupting peptide reduced activation, vascular leakage mice. TRAF2 from patients with co-localized VEGF. Our studies indicate (via TRAF2,3 signaling) an inducer triggers This work uncovered inhibition signaling as potential approach impair retinopathy.