Angiopoietin-like 7 Secretion Is Induced by Glaucoma Stimuli and Its Concentration Is Elevated in Glaucomatous Aqueous Humor

Kuchtey, John; Källberg, M. E.; Gelatt, Kirk N.; Rinkoski, Tommy A.; Komàromy, András M.; Kuchtey, Rachel W.

doi:10.1167/iovs.07-1347

Cited by 49 publications

(54 citation statements)

References 40 publications

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“…Both MYOC and ANGPTL-7 have previously been reported to be upregulated by GCs such as DEX. 57,58 In the present study, DEX added to HTM cells grown on hydrogels resulted in marked increases in mRNA expression of these two genes. Additionally, this DEX stimulated response of MYOC and ANGPTL-7 was even more striking in HTM cells grown on the pathomimetic substrates in comparison with the homeomimetic substrates.…”

Section: Discussionsupporting

confidence: 49%

Role of Substratum Stiffness in Modulating Genes Associated with Extracellular Matrix and Mechanotransducers YAP and TAZ

Raghunathan

Morgan

Dreier

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Primary open-angle glaucoma is characterized by increased resistance to aqueous humor outflow and a stiffer human trabecular meshwork (HTM). Two Yorkie homologues, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif, encoded by WWTR1 (TAZ), are mechanotransducers of the extracellular-microenvironment and coactivators of transcription. Here, we explore how substratum stiffness modulates the YAP/TAZ pathway and extracellular matrix genes in HTM cells and how this may be play a role in the onset and progression of glaucoma.METHODS. HTM cells from normal donors were cultured on hydrogels mimicking the stiffness of normal (5 kPa) and glaucomatous (75 kPa) HTM. Changes in expression of YAP/ TAZ related genes and steroid responsiveness were determined. Additionally, transglutaminase-2 expression was determined after YAP silencing.RESULTS. YAP and TAZ are both expressed in human trabecular meshwork cells. In vitro, YAP and TAZ were inversely regulated by substratum stiffness. YAP and 14-3-3r were downregulated to different extents on stiffer substrates; TAZ, tissue transglutaminase (TGM2), and soluble frizzled-related protein-1 (sFRP-1) were significantly upregulated. CTGF expression appeared to be altered differentially by both YAP and TAZ. Myocilin and angiopoietin-like 7 expression in response to dexamethasone was more pronounced on stiffer substrates. We demonstrated a direct effect by YAP on TGM2 when YAP was silenced by small interfering RNA.CONCLUSIONS. The expression of YAP/TAZ and ECM-relatedgenes is impacted on physiologically relevant substrates. YAP was upregulated in cells on softer substrates. Stiffer substrates resulted in upregulation of canonical Wnt modulators, TAZ and sFRP-1, and thus may influence the progression of glaucoma. These results demonstrate the importance of YAP/TAZ in the HTM and suggest their role in glaucoma. (Invest Ophthalmol Vis Sci.

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Section: Discussionsupporting

confidence: 49%

Role of Substratum Stiffness in Modulating Genes Associated with Extracellular Matrix and Mechanotransducers YAP and TAZ

Raghunathan

Morgan

Dreier

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…Kuchtey et al found that the concentration of ANGPTL7 was elevated in the AH of POAG eyes, supporting the notion that ANGPTL7 could be involved in POAG pathogenesis (24) . They concluded that elevated TGF-β 2 levels in glaucomatous AH could cause increased ANGPTL7 expression, which in turn could induce collagen changes, or through other mechanisms, contribute to the pathogenesis of POAG.…”

Section: Angptl7mentioning

confidence: 80%

Biomarkers in primary open angle glaucoma

Kokotas

Kroupis

Chiras

et al. 2012

Clinical Chemistry and Laboratory Medicine (CCLM)

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Glaucoma, a leading cause of blindness worldwide, is currently defi ned as a disturbance of the structural or functional integrity of the optic nerve that causes characteristic atrophic changes in the optic nerve, which may lead to specifi c visual fi eld defects over time. This disturbance usually can be arrested or diminished by adequate lowering of intraocular pressure (IOP). Glaucoma can be divided roughly into two main categories, ' open angle ' and ' closed angle ' glaucoma. Open angle, chronic glaucoma tends to progress at a slower rate and patients may not notice loss of vision until the disease has progressed signifi cantly. Primary open angle glaucoma (POAG) is described distinctly as a multifactorial optic neuropathy that is chronic and progressive with a characteristic acquired loss of optic nerve fi bers. Such loss develops in the presence of open anterior chamber angles, characteristic visual fi eld abnormalities, and IOP that is too high for the healthy eye. It manifests by cupping and atrophy of the optic disc, in the absence of other known causes of glaucomatous disease. Several biological markers have been implicated with the disease. The purpose of this study was to summarize the current knowledge regarding the non-genetic molecular markers which have been predicted to have an association with POAG but have not yet been validated.

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“…34 Thus, defects in secretion of myocilin and angiopoietin-like 7 proteins have been linked to the progression of POAG, and patients with ALS exhibit abnormal secretion of growth hormone and insulin-like growth factor. [85][86][87] Another approach would be to systematically analyze the role of Optn-interacting partners in the different Optn-associated pathologies. This could be applied to decipher the role of Golgi-associated Rab8 and Htt in Glaucoma or ALS.…”

Section: Subcellular Localization Of Optnmentioning

confidence: 99%