p38α MAPK-Mediated Redox Regulation of Transglutaminase 2 Drives Microvascular Leakage in Diabetic Retinas

초록

Microvascular leakage is an early hallmark of diabetic retinopathy (DR), but the redox-dependent mechanisms underlying this dysfunction remain unclear. Here, we investigated whether p38 alpha mitogen-activated protein kinase (MAPK) activates transglutaminase 2 (TGase2) through reactive oxygen species (ROS) generation, thereby promoting hyperglycemia-induced vascular permeability in diabetic retinas. In human retinal endothelial cells (HRECs), vascular endothelial growth factor (VEGF), which is elevated under hyperglycemic conditions, activated both p38 alpha MAPK and TGase2. VEGF-induced TGase2 activation was inhibited by the p38 MAPK inhibitor SB203580 or by p38 alpha MAPK siRNA. Similarly, VEGF-stimulated TGase2 activity in non-diabetic mouse retinas was blocked by knockdown of either p38 alpha MAPK or TGase2. In diabetic retinas, hyperglycemia-increased ROS production and TGase2 activity were reduced by SB203580 or p38 alpha MAPK siRNA, but not by the TGase inhibitor cystamine, indicating upstream ROS-dependent regulation. The antioxidant Trolox also suppressed TGase2 activation in VEGF-treated HRECs and diabetic retinas. Functionally, knockdown of p38 alpha MAPK or TGase2 preserved vascular endothelial (VE)-cadherin integrity and attenuated cytoskeletal remodeling in HRECs and diabetic retinas, resulting in reduced microvascular leakage. These findings identify a redox-dependent p38 alpha MAPK-TGase2 axis as a key mediator of retinal vascular permeability in DR and highlight this pathway as a potential therapeutic target for maintaining vascular integrity.

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