Angiopoietin-Like Protein 4 (ANGPTL4) Induces Retinal Pigment Epithelial Barrier Breakdown by Activating Signal Transducer and Activator of Transcription 3 (STAT3): Evidence from ARPE-19 Cells Under Hypoxic Condition and Diabetic Rats

Yang, Xiongwen; Cao, Jinfeng; Du, Yang; Gong, Qiang; Cheng, Yan; Su, Guanfang

doi:10.12659/msm.915748

“…ANGPTL4 is mainly expressed in the liver and plays a key role in inflammation, angiogenesis, and tumors. Recent studies have shown that ANGPTL4 is a therapeutic target for retinopathy of DR patients [ 18 ]. At the same time, this study also found that the levels of VEGF, MCP-1, and ANGPTL4 in the two groups decreased after treatment, and the levels of VEGF, MCP-1, and ANGPTL4 in the observation group were lower than those in the control group, suggesting that intravitreal injection of aflibercept in the treatment of DR with macular edema can improve the cytokine levels in the aqueous humor.…”

Section: Discussionmentioning

confidence: 99%

Clinical Comparative Study of Intravitreal Injection of Triamcinolone Acetonide and Aflibercept in the Treatment of Diabetic Retinopathy Cystoid Macular Edema

Yang

¹

,

Li

²

,

Yu

³

et al. 2022

Emergency Medicine International

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Objective To compare the curative effect of intravitreal injection of triamcinolone acetonide and aflibercept on diabetic retinopathy (DR) cystoid macular edema. Methods A total of 102 patients with DR cystoid macular edema admitted to the hospital were enrolled between July 2018 and July 2021. According to random number table method, they were divided into the control group (intravitreal injection of triamcinolone acetonide) and the observation group (intravitreal injection of aflibercept), 51 cases in each group. All were followed up for half a year. The clinical curative effect, visual acuity, central subfield macular thickness (CSMT), macular volume, scores of quality of life, and levels of cytokines in aqueous humor (vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), human angiopoietin-like protein 4 (ANGPTL4)] at different time points (before and at 6 months after surgery) were compared between the two groups. The times of drugs injection and occurrence of adverse reactions in both groups were statistically analyzed. Results The total effective rate in observation group was higher than that in the control group (96.08% vs 82.35%) ( P < 0.05 ). After 6 months of treatment, visual acuity was improved, and CSMT and macular volume were decreased in both groups. Also, the above changes were more significant in the observation group than those in the control group ( P < 0.05 ). After 6 months of treatment, levels of cytokines in aqueous humor were decreased in both groups. The levels of VEGF, MCP-1, and ANGPTL4 in observation group were lower than those in the control group ( P < 0.05 ). After 6 months of treatment, quality of life scores in observation group were higher than those in the control group ( P < 0.05 ). In the follow-up period, average times of drugs injection in the observation group were more than those in the control group, and the incidence of adverse reactions was lower than that in control group (5.88% vs 21.57%) ( P < 0.05 ). Conclusion The curative effect of intravitreal injection of both triamcinolone acetonide and aflibercept is good on DR cystoid macular edema. The curative effect of aflibercept is better, which can improve visual acuity and quality of life, and regulate cytokines in aqueous humor, with high safety. However, aflibercept has a high price, and further research is needed to determine whether its price can be matched with clinical benefits. In clinic, medication plan should be selected according to the actual situation.

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“…in addition, several signaling pathways, including the Pi3K/aKT, STaT3 and mTor signaling pathways, are associated with HiF-1α/VeGF signaling in dr (31)(32)(33). it has been reported that the Pi3K/aKT/mTor signaling pathway promotes dr via inducing retinal cell viability, apoptosis, migration and angiogenesis.…”

Section: Discussionmentioning

confidence: 98%

Mangiferin inhibits cell migration and angiogenesis via PI3K/AKT/mTOR signaling in high glucose‑ and hypoxia‑induced RRCECs

Shi

¹

,

Lv

²

,

Tang

³

et al. 2021

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Mangiferin is a prominent active component that can be derived from several traditional herbs, including Mangifera indica l., Anemarrhena asphodeloides Bge., and Belamcanda chinensis (l.) dc., which displays antidiabetic properties. diabetic retinopathy (dr), a serious complication caused by diabetes, is the leading cause of blindness. The present study aimed to evaluate the beneficial effects of mangiferin on high glucose (HG)/hypoxia-induced rat retinal capillary endothelial cell (rrcec) angiogenesis, as well as the underlying mechanisms. To establish an in vitro model of dr, rrcecs were exposed to 30 mM glucose and hypoxia. Following treatment with different doses of mangiferin (0.05, 0.1 or 0.2 µM), rrcec viability, migration and angiogenesis were assessed by performing cell counting Kit 8, immunofluorescence, wound healing, Transwell and tube formation assays. Western blotting was conducted to evaluate protein expression levels. Furthermore, lY294002 and iGF-1, an inhibitor and activator of the Pi3K/aKT/mTor signaling pathway, respectively, were used to verify the potential mechanisms underlying mangiferin. The results demonstrated that mangiferin notably inhibited HG/hypoxia-induced rrcec migration and angiogenesis. HG/hypoxia-induced upregulation of hypoxia-inducible factor-1α, vascular endothelial growth factor, matrix metallopeptidase (MMP)2 and MMP9 expression levels and the phosphorylation of Pi3K, aKT and mTOR in RRCECs was significantly reversed following treatment with mangiferin. additionally, further activation of the PI3K/AKT signaling pathway by IGF-1 inhibited the beneficial effects of mangiferin on rrcecs, whereas deactivation of the Pi3K/aKT signaling pathway by lY294002 displayed the opposite results. collectively, the results of the present study suggested that mangiferin suppressed rrcec angiogenesis via modulating the Pi3K/aKT/mTor signaling pathway, which could serve as an effective treatment strategy for dr.

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“…As an angiogenesis factor, ANGPTL4 promotes the pathological processes of diverse eye diseases by enhancing angiogenesis, vascular permeability, and inflammation [ 23 , 24 ]. Aqueous ANGPTL4 was obviously increased in PDR, inducing retinal neovascularization [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Aqueous Level of ANGPTL4 Correlates with the OCTA Metrics of Diabetic Macular Edema in NPDR

Xu

¹

,

Gong

²

,

Qiao

³

et al. 2022

Journal of Diabetes Research

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Purpose. To investigate the aqueous levels of angiogenic factors in nonproliferative diabetic retinopathy (NPDR) patients with diabetic macular edema (DME) and to ascertain their association with optical coherence tomography angiography (OCTA) metrics. Methods. This study enrolled 21 NPDR eyes with DME (NPDR/DME+), 17 NPDR eyes without DME (NPDR/DME-), and 16 diabetic eyes without retinopathy (DWR). Luminex bead-based multiplex array was used to measure the levels of 25 cytokines. OCTA system with a scan area of 3 × 3 mm was used to measure retinal thickness (RT), retinal volume (RV), superficial vessel density (SVD), deep vessel density (DVD), foveal avascular zone (FAZ) area, perimeter and acircularity index. Results. The levels of ANGPTL4 were significantly different among the three groups ( P < 0.05 ), in which NPDR/DME+ group had the highest level and NPDR/DME- group had a higher level than the DWR group (all, P < 0.0167 ). OCTA examination showed that, compared with DWR and NPDR/DME- group, RT and RV increased and the whole/parafoveal DVD decreased in NPDR/DME+ group (all, P < 0.05 ). Meanwhile, NPDR/DME- group had lower parafoveal DVD than the DWR group ( P < 0.05 ). Correlation analysis showed that the levels of ANGPTL4 were positively correlated with foveal/parafoveal RT and RV and negatively correlated with whole/parafoveal DVD in NPDR patients (all, P < 0.05 ). As the influencing factor of RT, RV, and DVD, every additional 103 pg/ml of ANGPTL4 was associated with an increase in foveal and parafoveal RT of 4.299 μm and 3.598 μm, respectively. Every additional 106 pg/ml of ANGPTL4 was associated with an increase in foveal and parafoveal RV of 3.371 mm3 and 17.705 mm3, respectively. Every additional 104 pg/ml of ANGPTL4 was associated with a decrease in whole and parafoveal DVD of 1.705% and 1.799%, respectively. Conclusions. The level of ANGPTL4 in aqueous humor of NPDR patients with DME was significantly increased and ANGPTL4 might predict RT, RV, and parafoveal DVD of DME in NPDR patients.

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Angiopoietin-Like Protein 4 (ANGPTL4) Induces Retinal Pigment Epithelial Barrier Breakdown by Activating Signal Transducer and Activator of Transcription 3 (STAT3): Evidence from ARPE-19 Cells Under Hypoxic Condition and Diabetic Rats

Cited by 14 publications

References 37 publications

Clinical Comparative Study of Intravitreal Injection of Triamcinolone Acetonide and Aflibercept in the Treatment of Diabetic Retinopathy Cystoid Macular Edema

Clinical Comparative Study of Intravitreal Injection of Triamcinolone Acetonide and Aflibercept in the Treatment of Diabetic Retinopathy Cystoid Macular Edema

Mangiferin inhibits cell migration and angiogenesis via PI3K/AKT/mTOR signaling in high glucose‑ and hypoxia‑induced RRCECs

Aqueous Level of ANGPTL4 Correlates with the OCTA Metrics of Diabetic Macular Edema in NPDR

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