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Matthias Zenkel, Daniel Berner, Ursula Hoja, Francesca Pasutto, Friedrich E Kruse, Ursula Schlotzer-Schrehardt; A potential role for impaired retinoic acid signaling in the pathophysiology of pseudoexfoliation syndrome/glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5666.
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© ARVO (1962-2015); The Authors (2016-present)
Recently, we identified retinoid X receptor alpha (RXRα) as a regulator of lysyl oxidase-like 1 (LOXL1), the main genetic risk factor for pseudoexfoliation (PEX) syndrome/glaucoma. To determine the pathophysiological role of retinoic acid (RA) signaling, we investigated the expression of key components of the RA pathway in tissue samples of PEX and control patients, and analyzed the effect of RA on the expression of PEX-related genes in vitro.
Ocular tissues from donor eyes with PEX syndrome and age-matched normal eyes were analyzed by qRT-PCR (n=24), Western blot analysis (n=4), and immunohistochemistry (n=4) for the expression of RA pathway genes. Aqueous humor and serum samples from PEX and age-matched cataract patients were analyzed by Western blot for extracellular components (n=8). The expression of LOXL1, fibrillin-1, elastin, and transforming growth factor ß1 (TGFß1) was analyzed in cultured human Tenon’s capsule fibroblasts (hTCF) and human trabecular meshwork cells (hTMC), after exposure to retinoic acid (2.5 µM) or following transfection with RXRα siRNA, using qRT-PCR (n=4).
Levels of STRA6 (stimulated by retinoic acid receptor 6), CRBP1 (cellular retinol-binding protein 1), CRABP2 (cellular retinoic acid-binding protein 2), RARα (retinoic acid receptor), and RXRα (retinoid X receptor) were significantly reduced, both on the mRNA (-40%; p<0.05) and protein level (-50%; p<0.01), in anterior segment tissues of PEX patients compared to controls. STRA6 prominently immunolocalized to iridal blood vessels and the pigmented ciliary epithelium, cell layers forming the blood-aqueous barrier. In PEX specimens, the reduced iridal and ciliary STRA6 staining was associated with LOXL1-positive PEX material deposits. Protein levels of the extracellular RBP4 (retinol binding protein 4) were significantly lower in aqueous humor (-40%; p<0.01) and serum (-25%; p<0.05) of PEX patients compared to controls. Knockdown of RXRα in hTCF and hTMC resulted in a significant upregulation of LOXL1, elastin, fibrillin-1, and TGFß1 compared to mock-transfected cells (+80%; p<0.01), whereas stimulation with RA significantly downregulated their expression (-50%; p<0.05).
These data suggest that impaired retinoic acid signaling is involved in the pathophysiology of PEX syndrome and promotes excessive matrix production and accumulation in PEX-associated fibrosis.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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