RESUMEN
Circulating inorganic phosphate exhibits a remarkable daily oscillation based on food intake. In humans and rodents, the daily oscillation in response to food intake may be coordinated to control the intestinal absorption, renal excretion, cellular shifts, and extracellular concentration of inorganic phosphate. However, mechanisms regulating the resulting oscillation are unknown. Here we investigated the roles of the sodium phosphate cotransporter SLC34 (Npt2) family and nicotinamide phosphoribosyltransferase (Nampt) in the daily oscillation of plasma inorganic phosphate levels. First, it is roughly linked to urinary inorganic phosphate excretion. Second, expression of renal Npt2a and Npt2c, and intestinal Npt2b proteins also exhibit a dynamic daily oscillation. Analyses of Npt2a, Npt2b, and Npt2c knockout mice revealed the importance of renal inorganic phosphate reabsorption and cellular inorganic phosphate shifts in the daily oscillation. Third, experiments in which nicotinamide and a specific Nampt inhibitor (FK866) were administered in the active and rest phases revealed that the Nampt/NAD+ system is involved in renal inorganic phosphate excretion. Additionally, for cellular shifts, liver-specific Nampt deletion disturbed the daily oscillation of plasma phosphate during the rest but not the active phase. In systemic Nampt+/- mice, NAD levels were significantly reduced in the liver, kidney, and intestine, and the daily oscillation (active and rest phases) of the plasma phosphate concentration was attenuated. Thus, the Nampt/NAD+ system for Npt2 regulation and cellular shifts to tissues such as the liver play an important role in generating daily oscillation of plasma inorganic phosphate levels.
Asunto(s)
Ritmo Circadiano , Citocinas/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismo , Fosfatos/sangre , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/metabolismo , Animales , Biomarcadores/sangre , Biomarcadores/orina , Citocinas/antagonistas & inhibidores , Citocinas/deficiencia , Citocinas/genética , Inhibidores Enzimáticos/farmacología , Femenino , Intestinos/enzimología , Riñón/enzimología , Hígado/enzimología , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , NAD/metabolismo , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Nicotinamida Fosforribosiltransferasa/deficiencia , Nicotinamida Fosforribosiltransferasa/genética , Fosfatos/orina , Eliminación Renal , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/deficiencia , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/deficiencia , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/deficiencia , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética , Factores de TiempoRESUMEN
Osteocytes orchestrate bone resorption and bone formation by controlling osteoclast and osteoblast activity. On the other hand, osteocytes secret FGF23 (fibroblast growth factor 23), FGF23 acts on the kidney to control phosphate homeostasis. Sclerostin is also released from osteocytes and it regulated osteoblast activity through Wnt/ß-catenin pathway. Therefore, an antibody that targets sclerostin is currently in phase- III clinical trials for the treatment of osteoporosis and it is expected as new therapeutics.