RESUMO
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-ß1/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-ß1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-ß1/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.
Assuntos
Síndrome de Exfoliação , Glaucoma de Ângulo Aberto , Síndrome de Exfoliação/genética , Síndrome de Exfoliação/metabolismo , Síndrome de Exfoliação/patologia , Glaucoma de Ângulo Aberto/metabolismo , Humanos , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Tretinoína/farmacologiaRESUMO
There is still no widely effective pharmacotherapy for alcohol addiction available in the clinic. FK506-binding protein 51 (FKBP51) is a negative regulator of the glucocorticoid receptor signaling pathway that regulates the stress-induced glucocorticoid feedback circuit. Here we asked whether selective inhibitors of FKBP51, exemplified by SAFit2, may serve as a new pharmacological strategy to reduce alcohol consumption and conditioned alcohol effects in a mouse model. We report that a relatively short treatment with SAFit2 (20 mg/kg, ip) reduces ongoing 16 vol% alcohol consumption when administered during free access to alcohol in a two-bottle free-choice test. SAFit2 was also able to reduce alcohol consumption when given during an abstinence period immediately before relapse. In contrast, SAFit2 did not affect alcohol consumption when given during a relapse period after repeated withdrawal from alcohol. SAFit2 (10 and 20 mg/kg, ip) showed no effects when used in an intermittent drinking schedule. When 20 vol% alcohol was only available every other day, SAFit2 had no effect on drinking, no matter whether given during a drinking episode or the day before. SAFit2 (2 and 20 mg/kg, ip) did not affect the expression of an alcohol-induced conditioned place preference (CPP). However, SAFit2 was able to inhibit alcohol-induced reinstatement of an extinguished CPP in a dose-dependent way. Altogether, these data may suggest pharmacological inhibition of FKBP51 as a viable strategy to reduce alcohol seeking and consumption.