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

## TL;DR

This study shows that p38α MAPK and TGase2, regulated by reactive oxygen species, contribute to blood vessel leakage in diabetic retinas, offering a new therapeutic target.

## Contribution

The paper identifies a novel redox-dependent p38α MAPK–TGase2 pathway driving microvascular leakage in diabetic retinopathy.

## Key findings

- p38α MAPK activates TGase2 through ROS generation in hyperglycemic conditions.
- Inhibiting p38α MAPK or TGase2 reduces vascular leakage in diabetic retinas.
- Antioxidants like Trolox suppress TGase2 activation and preserve vascular integrity.

## Abstract

Microvascular leakage is an early hallmark of diabetic retinopathy (DR), but the redox-dependent mechanisms underlying this dysfunction remain unclear. Here, we investigated whether p38α 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 p38α MAPK and TGase2. VEGF-induced TGase2 activation was inhibited by the p38 MAPK inhibitor SB203580 or by p38α MAPK siRNA. Similarly, VEGF-stimulated TGase2 activity in non-diabetic mouse retinas was blocked by knockdown of either p38α MAPK or TGase2. In diabetic retinas, hyperglycemia-increased ROS production and TGase2 activity were reduced by SB203580 or p38α 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 p38α 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 p38α 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.