Publication: Mecanismos celulares activados por receptores P2Y₂ en los procesos ciliares: implicaciones en la hipertensión ocular y el glaucoma
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2016-09-02
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Universidad Complutense de Madrid
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Abstract
El glaucoma es una neuropatía óptica crónica de etiología multifactorial, que provoca una pérdida progresiva e irreversible de la visión debida a la degeneración de los axones del nervio óptico y la muerte apoptótica de las células ganglionares de la retina (Downs et al., 2011; Quigley, 2011; Soto et al., 2014). Actualmente es la principal causa de ceguera irreversible en el mundo (Pascolini et al., 2012). Aunque su etiología aún no está clara, se sabe que el principal factor de riesgo para desarrollar la enfermedad es el aumento de la PIO debido a anomalías en la dinámica del humor acuoso (Casson et al., 2012). La presencia de receptores purinérgicos P2X y P2Y ha sido descrita en las principales estructuras oculares relacionadas con la producción y drenaje del humor acuoso, los procesos ciliares y la malla trabecular, que son bañadas por dicho fluido (Guzman-‐Aranguez et al., 2013). Al mismo tiempo, se ha referido la presencia del dinucleótido Ap4A, agonista de dichos receptores, en el humor acuoso, y cómo sus niveles se veían significativamente incrementados en pacientes glaucomatosos (Castany et al., 2011). El objetivo de esta tesis ha sido evaluar la implicación de los receptores purinérgicos P2Y2 de los procesos ciliares en la hipertensión ocular. Más concretamente determinar el papel del Ap4A a través de la activación de dichos receptores sobre la movilización del ion cloruro y del agua a través de las proteínas acuaporinas (AQPs), principales componentes del humor acuoso. Por otra parte, se ha investigado el origen de los niveles incrementados de Ap4A debidos al aumento de la PIO, caracterizando uno de los posibles sensores celulares implicados en dicho proceso. Al mismo tiempo se han evaluado y caracterizado los diferentes mecanismos implicados en dicha liberación...
Glaucoma is a multifactorial chronic optic neuropathy, characterized by the damage of the optic nerve head and progressive retinal ganglion cells death (Downs et al., 2011; Quigley, 2011; Soto et al., 2014). Currently, glaucoma is a leading cause of irreversible vision loss worldwide (Pascolini et al., 2012). Increased intraocular (IOP) pressure is a major risk factor of glaucoma development, due to anomalies in the aqueous humor dynamics(Casson et al., 2012). The expression of P2X and P2Y receptors has been described in the main structures related to aqueous humor inflow and outflow, the ciliary precess and trabecular meshwork (Guzman-‐Aranguez et al., 2013). At the same time, Ap4A, a purinergic receptor agonist, has been detected in the aqueous humor. The levels of Ap4A were around 15 times higher in glaucomatous patients than in healthy individuals (Castany et al., 2011). The aim of this PhD thesis has been to evaluate the role of P2Y2 receptor from ciliary processes on the IOP. More specifically, it has been studied to discover the involvement of Ap4A mediated by P2Y2 activation on chloride ion transport and water movement by aquaporins (AQPs), major components of the aqueous humor. Furthermore, a secondary objective was to investigate the origin of high levels of Ap4A, due to an increased IOP, and the possible mechanosensor participation on this process. At the same time, the main mechanism for this release has been evaluated and characterized. In vivo pharmacology and gen silencing assays, performed in New Zealand rabbits, demonstrated that P2Y2 receptor activation produces an increase of IOP, whereas the silencing by siRNA against P2Y2 produced about 50% of reduction on basal IOP, so the siRNA against P2Y2 receptor could be a new potential therapeutic agent to reduce IOP...
Glaucoma is a multifactorial chronic optic neuropathy, characterized by the damage of the optic nerve head and progressive retinal ganglion cells death (Downs et al., 2011; Quigley, 2011; Soto et al., 2014). Currently, glaucoma is a leading cause of irreversible vision loss worldwide (Pascolini et al., 2012). Increased intraocular (IOP) pressure is a major risk factor of glaucoma development, due to anomalies in the aqueous humor dynamics(Casson et al., 2012). The expression of P2X and P2Y receptors has been described in the main structures related to aqueous humor inflow and outflow, the ciliary precess and trabecular meshwork (Guzman-‐Aranguez et al., 2013). At the same time, Ap4A, a purinergic receptor agonist, has been detected in the aqueous humor. The levels of Ap4A were around 15 times higher in glaucomatous patients than in healthy individuals (Castany et al., 2011). The aim of this PhD thesis has been to evaluate the role of P2Y2 receptor from ciliary processes on the IOP. More specifically, it has been studied to discover the involvement of Ap4A mediated by P2Y2 activation on chloride ion transport and water movement by aquaporins (AQPs), major components of the aqueous humor. Furthermore, a secondary objective was to investigate the origin of high levels of Ap4A, due to an increased IOP, and the possible mechanosensor participation on this process. At the same time, the main mechanism for this release has been evaluated and characterized. In vivo pharmacology and gen silencing assays, performed in New Zealand rabbits, demonstrated that P2Y2 receptor activation produces an increase of IOP, whereas the silencing by siRNA against P2Y2 produced about 50% of reduction on basal IOP, so the siRNA against P2Y2 receptor could be a new potential therapeutic agent to reduce IOP...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Óptica y Optometría, Departamento de Bioquímica y Biología Molecular IV, leída el 28-01-2016