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Abstract #100820 Published in IGR 23-1
Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome
Zenkel M; Hoja U; Gießl A; Berner D; Hohberger B; Weller JM; König L; Hübner L; Ostermann TA; Gusek-Schneider GC; Kruse FE; Pasutto F; Schlötzer-Schrehardt UInternational journal of molecular sciences 2022; 23:
Pseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this study, we analyzed the role of the retinoic acid (RA) signaling pathway in the PEX-associated matrix metabolism and evaluated its targeting as a potential candidate for an anti-fibrotic intervention. We provided evidence that decreased expression levels of RA pathway components and diminished RA signaling activity occur in an antagonistic crosstalk with TGF-β1/Smad signaling in ocular tissues and cells from PEX patients when compared with age-matched controls. Genetic and pharmacologic modes of RA pathway inhibition induced the expression and production of PEX-associated matrix components by disease-relevant cell culture models in vitro. Conversely, RA signaling pathway activation by natural and synthetic retinoids was able to suppress PEX-associated matrix production and formation of microfibrillar networks via antagonization of Smad-dependent TGF-β1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-β1/Smad signaling is a driver of PEX-associated fibrosis, and that restoration of RA signaling may be a promising strategy for anti-fibrotic intervention in patients with PEX syndrome and glaucoma.
Department of Ophthalmology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
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