Overexpression of BMP4 protects retinal ganglion cells in a mouse model of experimental glaucoma

Li, Dongmei; Deng, Qinqin; Lei, Xin‐Lan; Lü, Wei; Zhao, Qingqing; Shen, Yin

doi:10.1016/j.exer.2021.108728

Cited by 12 publications

(3 citation statements)

References 49 publications

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“…In IOP‐dependent GC animal models, the IOP of the animals was found to increase with the imposition of inducing factors. Based on previous studies, (Liu et al, 2021; Tribble et al, 2021) we established a GC model in mice by using magnetic microbeads. Our data revealed that the levels of pathological damage, senescence, and apoptosis in retinal tissue were all notably enhanced in the GC model mice.…”

Section: Discussionmentioning

confidence: 99%

Insights into CD154‐mediated pathways in ocular hypertensive glaucoma: The role of Müller cells and P2X7 in retinal neuroprotection and therapeutic potential

Liu

Nie

et al. 2023

Cell Biology International

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An elevation of pathologic intraocular pressure (IOP) is the greatest risk factor for glaucoma. CD154 has been reported to bind to CD40 expressed by orbital fibroblasts and be involved in immune and inflammatory responses. However, the function and mechanism of CD154 in ocular hypertensive glaucoma (OHG) are not fully understood. We isolated and characterized Müller cells and subsequently examined the effect of CD154 on ATP release from those cells. After being cocultured with CD154-pretreated Müller cells, retinal ganglion cells (RGCs) were treated with P2X7 siRNAs or a P2X7 inhibitor. Furthermore, mouse models of glaucoma (GC) were injected with P2X7 shRNA. p21, p53, and P2X7 expression were examined, and cellular senescence and apoptosis were detected by β-Gal and TUNEL staining, retinal pathology was examined by H&E staining, and CD154 and β-Gal expression were detected by ELISA. CD154 induced ATP release from Müller cells and accelerated the senescence and apoptosis of RGCs that had been cocultured with Müller cells. We also found that treatment with P2X7 could attenuate the senescence and apoptosis of RGCs mediated by Müller cells pretreated with CD154. In vivo studies in GC model mice verified that P2X7 silencing attenuated pathological damage and prevented the senescence and apoptosis of retinal tissue. The study demonstrates how CD154 accelerates the aging and apoptosis of RGCs by co-cultivating Müller cells pretreated with CD154 in OHG. The research implies that CD154 has the potential to become a new therapeutic target for ocular hypertension glaucoma, providing a new research direction for its treatment.

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Section: Discussionmentioning

confidence: 99%

Insights into CD154‐mediated pathways in ocular hypertensive glaucoma: The role of Müller cells and P2X7 in retinal neuroprotection and therapeutic potential

Liu

Nie

et al. 2023

Cell Biology International

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“…These ndings support the potential involvement of the adaptor protein, TBKBP1, in the development of NTG. Bone Morphogenetic Protein 4 (BMP4) has been associated with retinal ganglion cell integrity in mouse models (Liu et al, 2021). However, the role of BMP4 in NTG remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide multi-ethnic meta-analysis identifies 22 independent risk loci for normal tension glaucoma and predominantly overlaps with high tension glaucoma.

Torres,

He,

et al. 2023

Preprint

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Background Primary open-angle glaucoma (POAG) is often divided into two subtypes. High-tension glaucoma (HTG) is characterized by elevated intraocular pressure (IOP), while normal-tension glaucoma (NTG) is characterized by IOP consistently in the normal range. However, this notion is still controversial as some studies argue that different tension subtypes is part of the same pathogenic process while other studies claim that NTG represents a different etiological process where primary neurodegeneration has a higher impact. This study aimed to elucidate the shared and distinct genetic architecture for NTG and HTG. Method To identify risk loci specific to NTG, we conducted a large international multi-ethnic multi-trait meta-analysis of 7,942 NTG cases and 384,431 controls without any form of glaucoma, and a structural measurement of the integrity of the optic nerve, vertical cup-to-disc ratio (VCDR, N = 282,100), adjusted for IOP using the mtCOJO method. We also performed an assessment of the genetic overlap between NTG and HTG (N HTG cases = 5144, N controls = 47,997) using the GWAS pairwise method (GWAS-PW). Findings: This study identified 22 risk loci associated with NTG. Of these, 17 loci are novel for NTG, and two loci, BMP4 and TBKBP1, have not previously been associated at the genome-wide significant level with glaucoma. The contribution of BMP4 in the development of NTG was further supported by integrating single-cell transcriptomic data from neuron-like cells, along with methylomic data from peripheral blood. Examination of each locus across the genome using the GWAS-PW method indicated that risk loci are shared across NTG and HTG. The magnitude of the effect of the genome-wide significant loci tends to be lower in NTG compared to their effects on HTG, particularly for IOP-related loci. Additionally, we identified 42 drug-gene interactions with four genes (ABCA1, CDKN2A, CDKN2B and ITGB3) that were prioritized through our gene-based analysis. Interpretation: This work expands our understanding of the genetics of NTG and highlights a strong genetic overlap between HTG and NTG. Despite the genetic overlap, we have shown that IOP-related loci tend to have a smaller effect size in NTG when compared with HTG whereas neurodegenerative loci independent of IOP have similar effect sizes on NTG and HTG. These results indicate that while there is a significant overlap in risk loci between NTG and HTG, a precise estimation of their effect sizes on NTG using larger studies could help develop genetic risk prediction models to identify individuals at a higher risk of developing NTG. We have also identified some potential targets for neuroprotective treatment through the interaction of four genes and multiple drugs. By harnessing multi-omics data, we substantiated the involvement of gene expression and DNA methylation of BMP4 in the etiology of NTG.

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“…Despite these interventional methods, some patients' vision further deteriorates due to the continued death of RGCs [12]. Numerous studies have tested small molecules and biologics against RGC death in experimental animal models of glaucoma [13][14][15][16]. Several of them have shown promising results.…”

Section: Introductionmentioning

confidence: 99%

Peptains block retinal ganglion cell death in animal models of ocular hypertension: implications for neuroprotection in glaucoma

et al. 2022

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Ocular hypertension is a significant risk factor for vision loss in glaucoma due to the death of retinal ganglion cells (RGCs). This study investigated the effects of the antiapoptotic peptides peptain-1 and peptain-3a on RGC death in vitro in rat primary RGCs and in mouse models of ocular hypertension. Apoptosis was induced in primary rat RGCs by trophic factor deprivation for 48 h in the presence or absence of peptains. The effects of intravitreally injected peptains on RGC death were investigated in mice subjected to retinal ischemic/reperfusion (I/R) injury and elevated intraocular pressure (IOP). I/R injury was induced in mice by elevating the IOP to 120 mm Hg for 1 h, followed by rapid reperfusion. Ocular hypertension was induced in mice by injecting microbeads (MB) or silicone oil (SO) into the anterior chamber of the eye. Retinal flatmounts were immunostained with RGC and activated glial markers. Effects on anterograde axonal transport were determined by intravitreal injection of cholera toxin-B. Peptain-1 and peptain-3a inhibited neurotrophic factor deprivation-mediated RGC apoptosis by 29% and 35%, respectively. I/R injury caused 52% RGC loss, but peptain-1 and peptain-3a restricted RGC loss to 13% and 16%, respectively. MB and SO injections resulted in 31% and 36% loss in RGCs following 6 weeks and 4 weeks of IOP elevation, respectively. Peptain-1 and peptain-3a inhibited RGC death; the loss was only 4% and 12% in MB-injected eyes and 16% and 15% in SO-injected eyes, respectively. Anterograde transport was defective in eyes with ocular hypertension, but this defect was substantially ameliorated in peptain-injected eyes. Peptains suppressed ocular hypertension-mediated retinal glial activation. In summary, our results showed that peptains block RGC somal and axonal damage and neuroinflammation in animal models of glaucoma. We propose that peptains have the potential to be developed as therapeutics against neurodegeneration in glaucoma.

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Overexpression of BMP4 protects retinal ganglion cells in a mouse model of experimental glaucoma

Cited by 12 publications

References 49 publications

Insights into CD154‐mediated pathways in ocular hypertensive glaucoma: The role of Müller cells and P2X7 in retinal neuroprotection and therapeutic potential

Insights into CD154‐mediated pathways in ocular hypertensive glaucoma: The role of Müller cells and P2X7 in retinal neuroprotection and therapeutic potential

Genome-wide multi-ethnic meta-analysis identifies 22 independent risk loci for normal tension glaucoma and predominantly overlaps with high tension glaucoma.

Peptains block retinal ganglion cell death in animal models of ocular hypertension: implications for neuroprotection in glaucoma

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