# Claudins in Retinal Disease: Beyond Barrier Integrity to Signaling and Therapy

## TL;DR

Claudins are crucial for retinal blood barriers and their disruption is linked to various retinal diseases, offering new therapeutic targets.

## Contribution

This paper provides a comprehensive review of claudin roles in retinal disease beyond barrier integrity, highlighting their signaling and therapeutic potential.

## Key findings

- Claudin isoforms show compartment-specific expression in inner and outer blood–retinal barriers.
- Disruption of claudin-mediated tight junctions is a common feature in multiple retinal diseases.
- Therapeutic strategies targeting claudin expression and localization are emerging for barrier repair.

## Abstract

What are the main findings?
Claudin family members exhibit compartment-specific expression and regulation across the inner and outer blood–retinal barriers.Disruption of Claudin-mediated tight junctions is a recurring feature across developmental, metabolic, inflammatory, and degenerative retinal conditions.

Claudin family members exhibit compartment-specific expression and regulation across the inner and outer blood–retinal barriers.

Disruption of Claudin-mediated tight junctions is a recurring feature across developmental, metabolic, inflammatory, and degenerative retinal conditions.

What are the implications of the main findings?
Claudins provide a unifying molecular framework linking retinal barrier dysfunction to disease progression.Understanding claudin-specific regulation may inform future strategies to monitor or stabilize blood–retinal barrier integrity in retinal diseases.

Claudins provide a unifying molecular framework linking retinal barrier dysfunction to disease progression.

Understanding claudin-specific regulation may inform future strategies to monitor or stabilize blood–retinal barrier integrity in retinal diseases.

The blood–retinal barrier (BRB) maintains neurovascular homeostasis by regulating solute and ion exchange between the retina and circulation. This selectivity depends on tight junctions (TJs), with claudin (Cldn) proteins forming the core structure that defines paracellular permeability. Distinct Cldn isoforms show cell-specific expression, with Cldn-5 predominating in the endothelial cells of the inner BRB and Cldn-19 is the signature Cldn in the retinal pigment epithelium forming the outer BRB. Disruption of these isoforms contributes to vascular leakage, inflammation, and neuronal loss across various ocular diseases. Cldn function in vascular homeostasis is multifaceted; barrier dysfunction does not always result from Cldn loss, as excessive expression or mislocalization, particularly of Cldn-5, can also impair BRB integrity. Cldns act as dynamic signaling hubs that respond to metabolic, oxidative, and mechanical stress and are regulated through VEGF, Wnt/β-catenin, and RhoA/ROCK pathways. This review summarizes current understanding of Cldn biology in retinal vascular regulation and highlights emerging therapeutic strategies aimed at stabilizing Cldn expression and junctional localization. Small molecules and blocking antibodies that enhance localization or prevent degradation are redefining barrier repair. Key questions remain regarding isoform specificity, inter-barrier communication, and systemic safety. Integrative omics and spatial imaging may reveal disease-specific Cldn signatures and guide molecular restoration of BRB integrity.