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N. Comes, W. Xue, T. Borras; Genes Upregulated After 7 D Sustained Elevated Pressure to the Trabecular Meshwork Reveal Angiopoietin–Like Factor CDTA as a Candidate for Outflow Resistance . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1853.
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© ARVO (1962-2015); The Authors (2016-present)
Conditions associated with glaucoma such as elevated intraocular pressure (IOP), dexamethasone (DEX) and TGFß2 induce a number of changes in the expression of human trabecular meshwork genes. Identifying such genes and their functions will provide a new set of causative candidates of the disease. Our goal was to study genes induced in the intact human TM after a sustained 7 days high IOP insult and correlate the most representative changes with those induced by DEX and TGFß2.
Anterior segment pairs from non–glaucomatous post–mortem human eyes were perfused for 24 h at constant flow of 3 µl/min with serum–free tissue culture medium. After achieving stable baseline, the flow in one eye was raised and maintain a ΔP of 35 mmHg for 7 days (two individuals). At the end of the experiment,100 ng of RNAs extracted from each individual TM were twice cycled for generation of cDNA and cRNA and hybridized to U95Av2 Affymetrix GeneChips (n=4). Paired comparisons between normotense and contralateral high IOP eyes were analyzed using the Affymatrix software. Genes most induced in both individuals and with a p–change value lower than 0.0001 were selected and crosschecked for their induction by other IOP insults, DEX and TGFß2.
Angiopoietin–like factor CDT6, an antiangiogenic/ECM deposition gene, was, after 7d, the most upregulated gene in one individual and among the ten most induced in the second (45–fold and 5–fold respectively). CDT6 was among the twelve most specifically–induced by DEX in HTM cells (28–fold), and the third most induced by TGFß2 (6–fold) (Zhao et al. IOVS 45, 4023, 2004). CDT6 maps to the GLC3B glaucoma locus. Other most upregulated genes at 7 d include Substance P and Secretogranin II (also induced after 6 h IOP), Matrix GLA (also induced after 2–4 d IOP) and the insulin–like factor somatomedin C. To a lesser extent, TIGR/MYOC and Optineurin (also induced by DEX) were too upregulated at 7d.
The screening and crosscheck of most upregulated genes under different glaucomatous conditions is beginning to reveal a set of genes whose functions appear to exhibit a good rationale for control of outflow resistance. The increased matrix deposition function associated with overexpression of CDT6, together with its GLC3B chromosome location are intriguing and would be further studied.
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