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Effect of IP-10/CXCR3 signaling pathway on rats with diabetic retinopathy
Fei Ji1, Hongjie Zhang2, Qian Ge3
1Department of Ophthalmology, Yancheng Third People's Hospital, Yancheng, China.. jifei1983@hotmail.com.
Abstract:
This study aimed to investigate the effect of the interferon-inducible protein-10 (IP-10)/C-X-C motif chemokine receptor 3 (CXCR3) signaling pathway on rats with diabetic retinopathy. A total of 21 Sprague-Dawley rats were selected as the objects and divided into control (n=7), model (n=7) and inhibitor (n=7) groups. The rats in control group did not receive any treatment. The diabetic retinopathy model was established using streptozotocin and vascular endothelial growth factor in model group, while the rats in inhibitor group were treated with AMG 487, an inhibitor of the IP-10/CXCR3 signaling pathway, based on the treatment in model group. The changes in gene expression patterns in rats with diabetic retinopathy were screened by sequencing. After the differential genes were determined, the pathways mainly related to the complication were obtained via enrichment analysis. The expression of the IP-10/CXCR3 signaling pathway, the apoptotic cells and the expression of inflammatory molecules (IL-6, IL-12, TNF-α and IL-1β) in each group of rats were detected. It was shown in volcano plot that there were some differentially expressed genes (fold change >1.2, P<0.01) in retinal tissues of rats in control and model groups. Meanwhile, the heatmap displayed that there were great differences in the gene expression patterns between control and model groups, and the gene expressions of IP-10 and CXCR3 in model group were higher than those in control group (P<0.05). The differential genes in control and model groupwere enriched in such processes as the cAMP metabolic regulatory pathway, chemotaxis of immunocytes, proliferation of endothelial cells, response of cytokine receptors, apoptosis, mTOR signaling pathway and TGF-β-related signaling pathway. The mRNA expressions of IP-10 and CXCR3 in model group were higher than those in control group (P<0.05), while they were notably lower in inhibitor group than those in model group (P<0.05). Besides, the protein levels of IP-10 and CXCR3 were identical to the mRNA levels. The apoptotic cells were increased markedly in model group compared with those in control group (P<0.05) and inhibitor group (P<0.05). Model group exhibited higher expression levels of IL-6, TNF-α and IL-1β in retinal tissues than control group (P<0.05), while inhibitor group had distinctly lower expression levels of IL-6, TNF-α and IL-1β in retinal tissues than model group (P<0.05). The IP-10/CXCR3 signaling pathway can affect rats with diabetic retinopathy.
Insights
The interferon-inducible protein-10 (IP-10)/C-X-C motif chemokine receptor 3 (CXCR3) pathway is implicated in diabetic retinopathy. Inhibiting this pathway reduced inflammation and apoptosis in rat models, suggesting a therapeutic target.
Area of Science:
- Ophthalmology and Molecular Biology
- Investigates the molecular mechanisms underlying diabetic retinopathy.
Background:
- Diabetic retinopathy is a serious complication of diabetes, leading to vision loss.
- The role of specific signaling pathways, such as interferon-inducible protein-10 (IP-10)/C-X-C motif chemokine receptor 3 (CXCR3), in diabetic retinopathy pathogenesis is not fully understood.
Purpose of the Study:
- To elucidate the effect of the IP-10/CXCR3 signaling pathway on rats with diabetic retinopathy.
- To evaluate the potential of inhibiting the IP-10/CXCR3 pathway as a therapeutic strategy.
Main Methods:
- Established a diabetic retinopathy model in Sprague-Dawley rats using streptozotocin and vascular endothelial growth factor.
- Divided rats into control, model, and inhibitor (treated with AMG 487, an IP-10/CXCR3 inhibitor) groups.
- Analyzed gene expression patterns, pathway enrichment, apoptosis, and inflammatory molecule expression (IL-6, IL-12, TNF-α, IL-1β).
Main Results:
- Significantly elevated IP-10 and CXCR3 gene and protein expression in the diabetic retinopathy model group compared to controls.
- Inhibition of the IP-10/CXCR3 pathway with AMG 487 markedly reduced IP-10 and CXCR3 expression.
- The inhibitor group showed reduced apoptotic cells and lower levels of inflammatory molecules (IL-6, TNF-α, IL-1β) compared to the model group.
Conclusions:
- The IP-10/CXCR3 signaling pathway plays a significant role in the development of diabetic retinopathy in rats.
- Inhibition of the IP-10/CXCR3 pathway demonstrates a therapeutic potential by mitigating inflammation and apoptosis in diabetic retinopathy.
