Science Translational Medicine | LRG1 Protein Drives Early Vascular Dysfunction in Diabetic Retinopathy

This study, for the first time, reveals the pathogenic role of LRG1 in the early stages of diabetic retinopathy, providing a new target for preventive therapies. By integrating animal models, cell experiments, and computational modeling, the research systematically elucidates the mechanisms by which LRG1 induces pericyte phenotypic transition and impairs hemodynamics via the TGFβ signaling pathway, offering a theoretical basis for early intervention strategies in diabetic retinopathy.

 

Literature Overview
This study, titled 'Leucine-rich α-2-glycoprotein 1 initiates the onset of diabetic retinopathy in mice', published in Science Translational Medicine, reviews and summarizes the molecular mechanisms underlying early vascular dysfunction in diabetic retinopathy (DR), with a particular focus on the systemic and local induction of LRG1 and its role in pericyte phenotypic transition. Using two diabetic mouse models (STZ and Ins2Akita), the study demonstrates that LRG1 expression occurs earlier than that of VEGF-A, and that its deletion or antibody blockade effectively alleviates early retinal pathology. This research identifies a potential target for early DR therapy and highlights LRG1 as a possible initiating factor.

Background Knowledge
Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness in the working-age population. The early phase of DR is characterized by retinal microvascular dysfunction, yet the mechanisms by which hyperglycemia disrupts microvascular homeostasis during this phase remain poorly understood, hindering the development of effective early treatments. LRG1 is a secreted glycoprotein known to play critical roles in TGFβ signaling, angiogenesis, and fibrosis. Previous studies have shown that LRG1 is upregulated in the plasma and vitreous of diabetic patients, but its expression and functional role in the retina have not been clearly defined. This study is the first to demonstrate the pathogenic role of LRG1 in the early stages of DR using animal and cell models, and it computationally models the impact of LRG1 on retinal blood flow and oxygen supply, further supporting its potential as a therapeutic target.

 

 

Research Methods and Experiments
The study utilized two diabetic mouse models: the STZ model (chemically induced type 1 diabetes) and the Ins2Akita model (spontaneous diabetes). LRG1 expression in the retina and plasma was analyzed using RNA in situ hybridization, immunofluorescence staining, qPCR, and Western blot. Chromatin immunoprecipitation (ChIP) was employed to assess NF-κB binding to the LRG1 promoter under high-glucose conditions in retinal endothelial cells. Retinal pericyte cultures, collagen gel contraction assays, and signaling pathway inhibitors were used to evaluate the impact of LRG1 on pericyte phenotypic transition. Computational modeling was used to analyze the effects of microvascular structural changes on blood flow and oxygen supply. In animal models, LRG1-blocking antibodies were used to assess therapeutic effects on retinal vascular permeability, vessel density, and electrophysiological function.

Key Conclusions and Perspectives

• LRG1 is upregulated early in the retina and plasma of diabetic mice, and its expression precedes that of VEGF-A, HIF1α, and TGFβ in Ins2Akita mice, suggesting it acts as an early initiating factor in DR.
• LRG1 is induced via the NF-κB pathway in retinal endothelial cells, and its deletion or blockade effectively reduces retinal microvascular leakage, vessel density loss, and basement membrane thickening.
• LRG1 promotes pericyte transition toward contractile and fibrotic phenotypes, mediated by ERK and SMAD2/3 signaling pathways, leading to pericyte contraction and myofibroblast-like transformation.
• Computational modeling reveals that LRG1-induced microvascular remodeling leads to reduced blood flow and tissue hypoxia, correlating with retinal electrophysiological dysfunction.
• In animal models, blocking LRG1 restored retinal electrophysiological function and improved microvascular structure, suggesting its feasibility as a therapeutic target.

Research Significance and Prospects
This study establishes LRG1 as a key pathogenic driver in the early stages of DR, providing experimental support for LRG1-targeted intervention strategies. Future research should further validate the source and expression mechanisms of LRG1 in the human retina and assess its potential as a biomarker and therapeutic target for early DR. Additionally, antibodies or small-molecule inhibitors targeting LRG1 may represent new tools for early DR intervention, particularly for preventing disease progression in patients who have not yet developed proliferative retinopathy.

 

 

Conclusion
This study identifies LRG1 as a critical driver in the early stages of diabetic retinopathy, with upregulated expression in both the retina and plasma. In animal models, deletion or blockade of LRG1 effectively alleviates early vascular dysfunction. The study also reveals that LRG1 induces pericyte phenotypic changes toward contraction and fibrosis via the TGFβ signaling pathway, leading to microvascular structural abnormalities and impaired hemodynamics. These findings provide a new molecular target for early intervention in diabetic retinopathy and lay the foundation for developing therapeutic strategies targeting LRG1. Future research should validate the expression pattern of LRG1 in human retinas and its correlation with disease progression, while exploring its translational potential as a biomarker and therapeutic target in clinical settings.

 

Giulia De Rossi, Ao-wang Qiu, Maxime Berg, John Greenwood, and Stephen E Moss. Leucine-rich α-2-glycoprotein 1 initiates the onset of diabetic retinopathy in mice. Science translational medicine.