Global Changes in Optic Nerve Head Gene Expression after Exposure to Elevated Intraocular Pressure in a Rat Glaucoma Model

Johnson, Elaine C.; Jia, Lijun; Cepurna, William O.; Doser, T. A.; Morrison, John C.

doi:10.1167/iovs.06-1282

Cited by 235 publications

(251 citation statements)

References 103 publications

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“…[39][40][41] Advances in biochemistry, chemistry, and engineering have enabled the development of new gene expression assays. 42 44 used microarray analysis to identify gene expression changes in the pressure-injured optic nerve head (ONH) in a rat glaucoma model. They found that the most significantly affected gene classes were cell proliferation, immune response, lysosome, cytoskeleton, extracellular matrix, and ribosomal.…”

Section: Genetic Terms and Approachesmentioning

confidence: 99%

“…The putative mechanisms of how this occurs are legion. They include pressureinduced injury of the ONH, leading to retinal gene expression alterations, 44,141 astrocyte response to changes in IOP, 142 oxidative stress, mitochondrial dysfunction, neurotrophic factors, 143,144 and autoimmunity. 145 Identifying validated genetic mutations that are replicated in multiple populations perhaps offers the best hope of correct identification of the most important pathways, which result in RGC death.…”

Section: Therapeutic Implications Of Genetics For Poagmentioning

confidence: 99%

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Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Gemenetzi

Yang

Lotery

2011

Eye

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Section: Genetic Terms and Approachesmentioning

confidence: 99%

Section: Therapeutic Implications Of Genetics For Poagmentioning

confidence: 99%

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Gemenetzi

Yang

Lotery

2011

Eye

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“…2, 15, 23). These studies identified changes in multiple genes/pathways related to immune responses, as well as structural and inflammatory changes in the ONH (8,24,25). The cause and impact of most of these changes in glaucoma remain to be determined, however.…”

mentioning

confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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“…Increase in collagen VI has also been proposed to increase the rate of collagen type I fibril formation (Harumiya et al, 2002;Minamitani et al, 2004;), result in loss of elastic properties (Hatamochi et al, 1996) and contribute to migration of glioblastoma cells . Elevated IOP models of glaucoma have demonstrated, the deposition of collagen I and VI at the optic nerve head to be an early event and are correlated linearly to degree of IOP-induced injury (Johnson et al, 2000;Guo et al, 2005;Morrison et al, 2005;Johnson et al, 2007). The ability of LC cells to respond to profibrotic triggers such as mechanical stress and transforming growth factor-β (TGF-β) resulting in enhanced ECM synthesis, implicates LC as an important pro-fibrotic tissue that could lead to loss of structural integrity resulting in collapse of LC and associated neuronal loss in gluacoma (Hernandez 2000 and.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa

Rao

Krishnamoorthy

Yorio

2008

Experimental Eye Research

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Endothelin-1(ET-1), a potent vaso-active peptide, mediates extracellular matrix regulation resulting in an increase in collagen deposition in various cell types and tissues and has been proposed to play a key role in glaucoma pathology. The role of ET-1 in the regulation of extracellular matrix collagens at the level of optic nerve head is not known. In this study we have examined the role of ET-1 in extracellular matrix collagen regulation in primary cultures of human lamina cribrosa cells. Our hypothesis is that ET-1 increases remodeling of the ECM of cells of the lamina cribrosa. Such actions could contribute to the development of optic neuropathy. QPCR analysis revealed that ET-1 mediated an increase in mRNA levels of collagen type I alpha 1 and collagen type VI alpha 1 chains at all doses of ET-1 with a significant increase at 1nM and 10nM concentration in LC cells. A dose dependent increase in collagen type I and type VI protein deposition and secretion was also observed by Western blot in response to ET-1 and was significant at 10nM and 100nM concentrations of ET-1. ET-1 increased the [ 3 H] proline uptake in LC cells suggesting that ET-1 contributed to an increase in total collagen synthesis in LC cells. ET-1 -mediated increase in collagen type I, type VI and total collagen synthesis was significantly blocked by the ET A receptor antagonist, BQ610, as well as with the ET B receptor antagonist, BQ788, suggesting the involvement of both receptor subtypes in ET-1 mediated collagen synthesis in LC cells. These results suggest that ET-1 regulates extra cellular matrix-collagen synthesis in LC cells and may contribute to ECM remodeling at the level of LC of POAG subjects who have elevated plasma and aqueous humor levels of endothelin-1.

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Global Changes in Optic Nerve Head Gene Expression after Exposure to Elevated Intraocular Pressure in a Rat Glaucoma Model

Abstract: In the ONH, pressure-induced injury results in cell proliferation and dramatically altered gene expression. For specific genes, expression levels were most altered by focal injury, suggesting that further array studies may identify initial, and potentially injurious, altered processes.

Cited by 235 publications

References 103 publications

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa

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