Erythropoietin Promotes Survival of Retinal Ganglion Cells in DBA/2J Glaucoma Mice

Zhong, Lihua; Bradley, Jeremy T.; Schubert, William; Ahmed, E; Adamis, Anthony P.; Shima, David T.; Robinson, G. A.; Ng, Y. Jack

doi:10.1167/iovs.06-0757

Cited by 132 publications

(91 citation statements)

References 47 publications

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“…NeuN is a DNA-binding protein that identifies most mature neuronal populations, and recent studies have used NeuN as a marker for RGCs in the GCL of the retina (Canola et al, 2007;Dijk et al, 2007;Zhong et al, 2007). In addition to RGCs, the GCL is comprised of a large number of displaced amacrine cells.…”

Section: Neun Can Be Used To Monitor Ganglion Cells In the Gclmentioning

confidence: 99%

“…NeuN has been used to identify neurons in the retina (Wang et al, 2000), with some groups observing NeuN expression exclusive to RGCs in the GCL (Canola et al, 2007;Dijk et al, 2007;Zhong et al, 2007). The GCL is comprised of approximately equal numbers of RGCs and displaced amacrine cells (Jeon et al, 1998), and, to date, there has not been a study that presents evidence for the unequivocal absence of NeuN in displaced amacrine cells.…”

Section: Neun-positive Rgcs Persist Through Axon Degenerationmentioning

confidence: 99%

See 1 more Smart Citation

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Buckingham¹,

Inman²,

Lambert³

et al. 2008

J. Neurosci.

376

336

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Glaucoma is characterized by retinal ganglion cell (RGC) pathology and a progressive loss of vision. Previous studies suggest RGC death is responsible for vision loss in glaucoma, yet evidence from other neurodegenerative diseases suggests axonal degeneration, in the absence of neuronal loss, can significantly affect neuronal function. To characterize RGC degeneration in the DBA/2 mouse model of glaucoma, we quantified RGCs in mice of various ages using neuronal-specific nuclear protein (NeuN) immunolabeling, retrograde labeling, and optic nerve axon counts. Surprisingly, the number of NeuN-labeled RGCs did not decline significantly until 18 months of age, at which time a significant decrease in RGC somal size was also observed. Axon dysfunction and degeneration occurred before loss of NeuN-positive RGCs, because significant declines in RGC number assayed by retrograde tracers and axon counts were observed at 13 months. To examine whether axonal dysfunction/degeneration affected gene expression in RGC axons or somas, NeuN and neurofilament-heavy (NF-H) immunolabeling was performed along with quantitative reverse transcription-PCR for RGC-specific genes in retinas of aged DBA/2 mice. Although these mice had similar numbers of NeuN-positive RGCs, the expression of neurofilament light, Brn-3b, and Sncg mRNA varied; this variation in RGC-specific gene expression was correlated with the appearance of NF-H immunoreactive RGC axons. Together, these data support a progression of RGC degeneration in this model of glaucoma, beginning with loss of retrograde label, where axon dysfunction and degeneration precede neuronal loss. This progression of degeneration suggests a need to examine the RGC axon as a locus of pathology in glaucoma.

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Section: Neun Can Be Used To Monitor Ganglion Cells In the Gclmentioning

confidence: 99%

Section: Neun-positive Rgcs Persist Through Axon Degenerationmentioning

confidence: 99%

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Buckingham¹,

Inman²,

Lambert³

et al. 2008

J. Neurosci.

376

336

View full text Add to dashboard Cite

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“…Therefore, factors other than ischemia must be involved in the primary regulation of Epo production in the human retina. Regarding the Epo receptor (EpoR), its expression has been detected in the mouse retina (8,13) and in the human fetal retina (14), but until now it has not been investigated in the adult human retina.…”

mentioning

confidence: 99%

Expression of Erythropoietin and Its Receptor in the Human Retina

2008

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OBJECTIVE -The purpose of this study was to evaluate erythropoietin (Epo) and Epo receptor (EpoR) expression in the retina and in vitreous fluid from diabetic and nondiabetic donors. To gain insight into the mechanisms responsible for the regulation of Epo production in the retina, we also assessed retinal expression of hypoxia-inducible factors (HIF-1␣ and HIF-2␣).RESEARCH DESIGN AND METHODS -Eighteen postmortem eyes from 9 diabetic patients without clinically detectable retinopathy were compared with 18 eyes from 9 nondiabetic donors. mRNA of Epo, HIF-1␣, and HIF-2␣ (quantitative RT-PCR) were measured separately in neuroretina and retinal pigment epithelium (RPE). Epo and EpoR were assessed in the retina (immunofluorescence by confocal laser microscopy) and in the vitreous fluid (radioimmunoassay and enzyme-linked immunosorbent assay, respectively).RESULTS -Epo and EpoR mRNAs were significantly higher in the RPE than in the neuroretina. Higher expression of Epo was detected in the retinas (both in the RPE and in the neuroretina) from diabetic donors. By contrast, EpoR expression was similar in both groups. We did not find any difference in HIF-1␣ and HIF-2␣ mRNA expression between diabetic and nondiabetic donors (both in RPE and neuroretina). Intravitreal Epo concentration was higher in diabetic donors than in nondiabetic control subjects. However, EpoR concentrations were similar in both groups.CONCLUSIONS -Epo overexpression is an early event in the retina of diabetic patients, and this is not associated with any change in EpoR. At this early stage, other factors apart from hypoxia seem to be more important in accounting for the Epo upregulation that exists in the diabetic retina. Diabetes Care 31:1189-1194, 2008E rythropoietin (Epo) was first described as a glycoprotein produced exclusively in fetal liver and adult kidney that acts as a major regulator of erythropoiesis (1). However, Epo expression has been found in the human brain (2), and, recently, we have demonstrated that Epo mRNA also exists in the adult human retina (3). Epo has a potent neuroprotective effect in the brain as well as in the retina (4,5).The retina is the most metabolically active tissue in the human body and, therefore, is highly sensitive to reductions in oxygen tension. Hypoxia-inducible factor (HIF) is the primary hypoxic signaling protein in cells for regulating angiogenesis and is able to induce the transcription of more than 70 genes, such as Epo (6). Indeed, HIF was discovered during studies of the regulation of Epo (7). Hypoxia is a major stimulus for both systemic (1) and intraocular Epo production (8), and high intravitreous levels of Epo have been reported in ischemic retinal diseases such as proliferative diabetic retinopathy (9 -11). In addition, it has been reported that Epo has an angiogenic potential equivalent to that of vascular endothelial growth factor (11,12). However, we also found elevated intravitreal levels of Epo in patients with diabetic macular edema, a condition in which neither hypoxia nor angiogenesis i...

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“…EPO has been extensively studied for its neuroprotective role for the past 10 years, but the regulation mechanisms have not been understood at the molecular level [Brines and Cerami, 2005;Calapai et al, 2000;Jelkmann 2007;Kanaan et al, 2006;Kawakami et al, 2001;Li et al, 2007;Mauer 1965;Miyake et al, 1977;Yamaji et al, 1996;Zhong et al, 2007]. Previous approaches using the in vivo mice model was not satisfactory, because the EPO knockout mice model is lethal.…”

Section: Neuroprotective Erythropoietin (Epo)mentioning

confidence: 99%

“…EPO promotes survival of RGCs in a glaucoma mouse model [Zhong et al, 2007], and stimulates neurogenesis and post-stroke recovery [Tsai et al, 2006]. In vitro models reveal that EPO stimulates neuritic outgrowth by postnatal [Böcker-Meffert et al, 2002] and adult RGCs [Kretz et al, 2005].…”

Section: Neuroprotective Erythropoietin (Epo)mentioning

confidence: 99%

New Biomarkers in the Retina and RPE Under Oxidative Stress

Jahng¹

2012

Ocular Diseases

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Erythropoietin Promotes Survival of Retinal Ganglion Cells in DBA/2J Glaucoma Mice

Abstract: EPO promoted RGC survival in DBA/2J glaucomatous mice without affecting IOP. These results suggest that EPO may be a potential therapeutic neuroprotectant in glaucoma.

Cited by 132 publications

References 47 publications

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Progressive Ganglion Cell Degeneration Precedes Neuronal Loss in a Mouse Model of Glaucoma

Expression of Erythropoietin and Its Receptor in the Human Retina

New Biomarkers in the Retina and RPE Under Oxidative Stress

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