Restoration of the Inner Blood–Retinal Barrier in Diabetic Retinopathy Through Norrin-FZD4 Signaling
- 1Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Ann Arbor, MI 48105, USA
Abstract
Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in the working-age population and is characterized by the disruption of the blood–retinal barrier (BRB) integrity and increased vascular permeability. Elevated vascular endothelial growth factor (VEGF) contributes to BRB dysfunction in DR. Current therapies for DR, including anti-VEGF agents, have provided significant clinical benefits; however, not all patients respond optimally, highlighting the need for new therapeutic approaches. Norrin, an endogenous cytokine essential for blood–retinal barrier development and maintenance, has emerged as a potential therapeutic target for restoring barrier function in retinal vascular disease. In this review, we summarize the evidence supporting norrin signaling as a mechanism for restoring BRB properties following VEGF-induced barrier disruption and in DR, as well as its role in preserving visual function. We also discuss the development of engineered FZD4 agonists designed to mimic or enhance norrin signaling, providing a therapeutic strategy to activate this pathway independently of endogenous norrin. Together, these findings highlight norrin-FZD4 signaling as a potential therapeutic approach to restore BRB integrity and preserve vision in DR and other blinding diseases associated with BRB dysfunction.
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BibTeX
@article{gonzalezgonzalez2026restoration,
title = {{Restoration of the Inner Blood–Retinal Barrier in Diabetic Retinopathy Through Norrin-FZD4 Signaling}},
author = {Laura González-González and David A. Antonetti},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219849},
url = {https://www.mdpi.com/1422-0067/27/21/9849},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Restoration of the Inner Blood–Retinal Barrier in Diabetic Retinopathy Through Norrin-FZD4 Signaling
AU - Laura González-González
AU - David A. Antonetti
PY - 2026
DA - 2026/11/03
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219849
UR - https://www.mdpi.com/1422-0067/27/21/9849
AB - Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in the working-age population and is characterized by the disruption of the blood–retinal barrier (BRB) integrity and increased vascular permeability. Elevated vascular endothelial growth factor (VEGF) contributes to BRB dysfunction in DR. Current therapies for DR, including anti-VEGF agents, have provided significant clinical benefits; however, not all patients respond optimally, highlighting the need for new therapeutic approaches. Norrin, an endogenous cytokine essential for blood–retinal barrier development and maintenance, has emerged as a potential therapeutic target for restoring barrier function in retinal vascular disease. In this review, we summarize the evidence supporting norrin signaling as a mechanism for restoring BRB properties following VEGF-induced barrier disruption and in DR, as well as its role in preserving visual function. We also discuss the development of engineered FZD4 agonists designed to mimic or enhance norrin signaling, providing a therapeutic strategy to activate this pathway independently of endogenous norrin. Together, these findings highlight norrin-FZD4 signaling as a potential therapeutic approach to restore BRB integrity and preserve vision in DR and other blinding diseases associated with BRB dysfunction.
SN - 1422-0067
ER -