RESUMEN
The megalin/cubilin receptor complex is required for proximal tubular endocytosis and degradation of filtered albumin. An additional high-capacity retrieval pathway of intact albumin for the recovery of large amounts of filtered albumin has been proposed, possibly involving cooperation between megalin/cubilin and the neonatal Fc receptor. To clarify the potential role of such a pathway, we examined the effects of megalin/cubilin gene inactivation on tubular albumin uptake and plasma albumin levels in nephrotic, podocin knockout mice. Immunofluorescence microscopy of megalin/cubilin/podocin knockout mouse kidneys demonstrated abolishment of proximal tubule albumin uptake, in contrast to the excessive albumin accumulation observed in podocin knockout mice compared to controls. Correspondingly, urinary albumin excretion was increased 1.4 fold in megalin/cubilin/podocin compared to podocin knockout mice (albumin/creatinine: 226 vs. 157 mg/mg). However, no difference in plasma albumin levels was observed between megalin/cubilin/podocin and podocin knockout mice, as both were reduced to approximately 40% of controls. There were no differences in liver albumin synthesis by mRNA levels and protein abundance. Thus, megalin/cubilin knockout efficiently blocks proximal tubular albumin uptake in nephrotic mice but plasma albumin levels did not differ as a result of megalin/cubilin-deficiency, suggesting no significance of the megalin/cubilin-pathway for albumin homeostasis by retrieval of intact albumin.
Asunto(s)
Albuminuria/metabolismo , Endocitosis , Túbulos Renales Proximales/metabolismo , Síndrome Nefrótico/metabolismo , Albúmina Sérica/metabolismo , Albuminuria/sangre , Albuminuria/genética , Albuminuria/orina , Animales , Creatinina/orina , Modelos Animales de Enfermedad , Femenino , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Hígado/metabolismo , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/deficiencia , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Síndrome Nefrótico/sangre , Síndrome Nefrótico/genética , Síndrome Nefrótico/orina , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genéticaRESUMEN
The gravitationally lensed supernova Refsdal appeared in multiple images produced through gravitational lensing by a massive foreground galaxy cluster. After the supernova appeared in 2014, lens models of the galaxy cluster predicted that an additional image of the supernova would appear in 2015, which was subsequently observed. We use the time delays between the images to perform a blinded measurement of the expansion rate of the Universe, quantified by the Hubble constant (H0). Using eight cluster lens models, we infer [Formula: see text]. Using the two models most consistent with the observations, we find [Formula: see text]. The observations are best reproduced by models that assign dark-matter halos to individual galaxies and the overall cluster.
RESUMEN
In 1964, Refsdal hypothesized that a supernova whose light traversed multiple paths around a strong gravitational lens could be used to measure the rate of cosmic expansion. We report the discovery of such a system. In Hubble Space Telescope imaging, we have found four images of a single supernova forming an Einstein cross configuration around a redshift z = 0.54 elliptical galaxy in the MACS J1149.6+2223 cluster. The cluster's gravitational potential also creates multiple images of the z = 1.49 spiral supernova host galaxy, and a future appearance of the supernova elsewhere in the cluster field is expected. The magnifications and staggered arrivals of the supernova images probe the cosmic expansion rate, as well as the distribution of matter in the galaxy and cluster lenses.