Altered Peripheral Sensitivity to Glucocorticoids in Primary Open-Angle Glaucoma

Stokes, John B.; Walker, Brian R.; Campbell, Jill C.; O’Brien, Colm; Andrew, Ruth

doi:10.1167/iovs.02-1318

Cited by 27 publications

(17 citation statements)

References 40 publications

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“…Furthermore, patients with POAG may exhibit increased peripheral vascular sensitivity to glucocorticoids resulting in enhanced local adverse effect in the eye. 3 Adverse effects of facial steroids on the eye have been reported. 4 Risk factors 5 for developing IOP rise include: pre-existing history or family history of POAG, type 1 diabetes, connective tissue disorder such as rheumatoid arthritis, or high myopia.…”

Section: Discussionmentioning

confidence: 99%

Irreversible visual loss secondary to excessive topical steroid use in eczema

Fat

Leslie

2011

Br J Gen Pract

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Section: Discussionmentioning

confidence: 99%

Irreversible visual loss secondary to excessive topical steroid use in eczema

Fat

Leslie

2011

Br J Gen Pract

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“…Nevertheless, in the human intraocular environment, high ratios of AH cortisol:cortisone indicate a functional intraocular 11b-HSD1 (cortisone/ cortisol) (Rauz et al 2001(Rauz et al , 2003b, endorsed by a reduction in IOP (therefore AH secretion) after systemic inhibition of 11b-HSD1. Furthermore, both 11b-HSD1 and -2 activities have been shown in whole rat eye homogenates (Stokes et al 2000) and abnormal urinary corticosteroid metabolites indicative of 11b-HSD dysregulation are also seen in patients with primary open-angle glaucoma compared with controls (Stokes et al 2003).…”

Section: Western Blot Analysesmentioning

confidence: 99%

“…Furthermore, high ratios of AH cortisol:cortisone reflect a functional intraocular 11b-HSD1 (cortisone/cortisol) (Rauz et al 2001(Rauz et al , 2003b) and a significant reduction (15-20%) in IOP following systemic inhibition of 11b-HSD1 with the non-selective inhibitor, carbenoxolone, has been established in both 'normal' volunteers (Rauz et al 2001) and patients with low to moderate risk ocular hypertension (patients with raised IOP without optic neuropathy) (Rauz et al 2003b). In addition, patients with primary open-angle glaucoma (a prevalent, sight-threatening disease associated with uncontrolled IOP and optic nerve damage) exhibit increased peripheral vascular sensitivity to GCs and the ratio of urinary cortisol to cortisone metabolites has been found to be elevated in these patients versus normal controls (Stokes et al 2003). These data support the role of 11b-HSDs in IOP homeostasis and the pathogenesis of primary open-angle glaucoma, thereby providing a possible therapeutic target for the treatment of patients with uncontrolled IOP.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

Onyimba¹,

Vijapurapu²,

Curnow³

et al. 2006

Journal of Endocrinology

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The prereceptor regulation of glucocorticoids (GCs) by 11b-hydroxysteroid dehydrogenase type-1 (11b-HSD1), a bidirectional isozyme that interconverts active (cortisol) and inactive (cortisone) GCs, is an established determinant of GC function in tissues such as liver, adipose and bone. Although the therapeutic use of GCs is abundant in ophthalmic practice, where GC interactions with nuclear receptors modulate gene transcription, the prereceptor regulation of endogenous cortisol is not well described in ocular tissues. Recent descriptive studies have localised 11b-HSD1 to the human corneal epithelium and non-pigmented epithelium (NPE) of the ciliary body, indicating a link to corneal epithelial physiology and aqueous humour production. In this study, we characterise the functional aspects of the autocrine regulation of GCs in the anterior segment of the rabbit eye. Using our in-house generated primary antibody to human 11b-HSD1, immunohistochemical analyses were performed on paraffin-embedded sections of whole New Zealand white albino rabbits, (NZWAR) eyes. As in human studies, 11b-HSD1 was localised to the corneal epithelium and the NPE. No staining was seen in the albino 'pigmented' ciliary epithelium. Specific enzyme assays for oxo-reductase (cortisone/cortisol) and dehydrogenase (cortisol/cortisone) activity indicated predominant 11b-HSD1 oxo-reductase activity from both the intact ciliary body tissue (nZ12, median 2$1 pmol/mg per h and range 1$25-2$8 pmol/mg per h; PZ0$006) and primary cultures of corneal epithelial cells (nZ12, median 3$0 pmol/mg per h and range 1$0-7$4 pmol/mg per h, PZ0$008) compared with dehydrogenase activity (median 1$0 pmol/mg per h and range 0$5-2$0 pmol/mg per h; median 0$5 pmol/mg per h and range 0$25-1$9 pmol/mg per h respectively). These findings were supported by expression of 11b-HSD1 protein as visualised by Western blotting of ciliary body tissue and immunocytochemistry of corneal epithelial cells. Reduction of corneal epithelial cell proliferation was seen after primary cultures were co-incubated with cortisol and cortisone. 11b-HSD1 activity was not demonstrated in naïve conjunctival fibroblasts or corneal stromal keratocytes. Our results indicate that the distribution of 11b-HSD1 in the rabbit resembles that of the human eye and activates cortisone to cortisol in both corneal and uveal tissues. The NZWAR provides a suitable in vivo model for the further evaluation of 11b-HSD1 activity in the eye, especially its role in corneal epithelial and ciliary body physiology.

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“…Approximately 30% to 40% of people treated with GCs develop elevated IOP (referred to as steroid responders), and this is a causal risk factor for glaucoma. 21,22 Dexamethasone (DEX) has been widely used in vitro to investigate the mechanisms underlying GC-induced glaucoma [23][24][25][26][27] in the HTM. Myocilin (MYOC) and angiopoietin like protein 7 (ANGPTL7) are two ECM proteins significantly increased in expression in glaucoma as well as in response to GC treatment of HTM cells.…”

mentioning

confidence: 99%

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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Altered Peripheral Sensitivity to Glucocorticoids in Primary Open-Angle Glaucoma

Abstract: Patients with POAG exhibit increased peripheral vascular sensitivity to glucocorticoids. Increased sensitivity of glucocorticoid receptors, may enhance local glucocorticoid action in the eye and exacerbate the adverse effects of glucocorticoids in this condition.

Cited by 27 publications

References 40 publications

Irreversible visual loss secondary to excessive topical steroid use in eczema

Irreversible visual loss secondary to excessive topical steroid use in eczema

Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye

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

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