RESUMEN

Hypoxia upregulates hypothalamic corticotrophin releasing hormone (CRH) and its receptor type-1 (CRHR1) expression and activates the HPA axis and induces hypoxic sickness and behavioral change. The transcriptional mechanism by which hypoxia differently regulates CRHR1 expression remains unclear. Here we report hypoxia time-dependently induced biphasic expression of CRHR1mRNA in rat pituitary during different physiological status. Short exposure of gestational dams to hypoxia reduced CRHR1mRNA in the pituitary of P1-P14 male rat offspring. A short- and prolonged-hypoxia evoked biphasic response of CRHR1mRNA characterized initially by decreases and subsequently by persistent increases, mediated by a rapid negative feedback via CRHR1 signaling and positive transcriptional control via NF-κB, respectively. Further analysis of CRHR1 promoter in cultured primary anterior pituitary and AtT20 cells showed that c-Jun/AP-1 delivered negative while HIF-1α and NF-κB delivered positive control of transcription at CRHR1 promoter. The negative and positive inputs are integrated by hypoxic initiation and duration in CRHR1 transcription.

Asunto(s)

Hipófisis/patología , Receptores de Hormona Liberadora de Corticotropina/genética , Transducción de Señal , Transcripción Genética , Animales , Encéfalo/embriología , Hipoxia de la Célula/genética , Línea Celular , Metilación de ADN/genética , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Modelos Biológicos , FN-kappa B/metabolismo , Embarazo , Regiones Promotoras Genéticas/genética , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Factor de Transcripción AP-1/metabolismo