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Gillian J McLellan, Kazuya Oikawa; Optic Nerve Head (ONH) TGF-β in a Spontaneous Large Animal Glaucoma Model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2547.
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TGF-β has been widely implicated as playing a key role in pathologic fibrosis and gliosis associated with ONH remodeling and axon loss in human glaucoma patients and in monkey experimental glaucoma, but increased expression of this cytokine has not been a consistent finding in rodent models. The purpose of our study was to determine if ONH TGF-β expression is increased in recessively inherited feline congenital glaucoma (FCG), a model with ONH and lamina cribrosa (LC) structure similar to humans.
Relative intensities of immunofluorescence (IF) labeling of TGF-β2, normalized to negative controls, were compared in the retinal nerve fiber layer (RNFL), and anterior, LC and retro-laminar regions of the ONH, in cryosections from five adult and four 3mo FCG cats (homozygous for LTBP2 mutation) and from four adult and three 3mo normal, wt cats. Equal amounts of ONH proteins from an additional three FCG and four normal wt adult cats, as well as an adult cat treated in vivo with an oral AT-1 blocker, were separated on SDS-PAGE gels, with appropriate controls, and transferred to PVDF membranes for semi-quantitative immunoblotting (normalized to loading control). Values were compared between groups, by region and by age (unpaired t-test; Bonferroni corrected p values <0.0125 considered significant)
Intensity of IF-labeling for TGF-β2 was significantly higher in all regions of the ONH in adult cats with FCG compared to age-matched, wt controls. Immunoblotting results were consistent with these IF data. An approximately four-fold increase in ONH TGF-β2 expression relative to normal subjects was consistently observed in adult FCG cats. Oral AT-1 blockade mitigated this glaucoma-associated increase in ONH TGF-β2. No significant increase in ONH TGF-β2 was observed in 3mo cats with FCG compared to wt controls. Expression of TGF-β2 was lower in 3mo cats than in adult cats, regardless of their glaucoma status.
Our data support a role for TGF-β2 in the pathobiology of glaucomatous optic neuropathy. Elevated TGF-β2 was not a prominent feature of early disease. Initial results suggest that chronic FCG represents a valuable, “large eyed”, translational model in which to study therapeutic strategies that target TGF-β expression and signaling in the glaucomatous ONH.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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