Distinct functions of megalin and cubilin receptors in recovery of normal and nephrotic levels of filtered albumin.
Am J Physiol Renal Physiol
; 318(5): F1284-F1294, 2020 05 01.
Article
en En
| MEDLINE
| ID: mdl-32200668
Proximal tubule (PT) cells express a single saturable albumin-binding site whose affinity matches the estimated tubular concentration of albumin; however, albumin uptake capacity is greatly increased under nephrotic conditions. Deciphering the individual contributions of megalin and cubilin to the uptake of normal and nephrotic levels of albumin is impossible in vivo, as knockout of megalin in mice globally disrupts PT endocytic uptake. We quantified concentration-dependent albumin uptake in an optimized opossum kidney cell culture model and fit the kinetic profiles to identify albumin-binding affinities and uptake capacities. Mathematical deconvolution fit best to a three-component model that included saturable high- and low-affinity uptake sites for albumin and underlying nonsaturable uptake consistent with passive uptake of albumin in the fluid phase. Knockdown of cubilin or its chaperone amnionless selectively reduced the binding capacity of the high-affinity site, whereas knockdown of megalin impacted the low-affinity site. Knockdown of disabled-2 decreased the capacities of both binding sites. Additionally, knockdown of megalin or disabled-2 profoundly inhibited the uptake of a fluid phase marker, with cubilin knockdown having a more modest effect. We propose a novel model for albumin retrieval along the PT in which cubilin and megalin receptors have different functions in recovering filtered albumin in proximal tubule cells. Cubilin binding to albumin is tuned to capture normally filtered levels of the protein. In contrast, megalin binding to albumin is of lower affinity, and its expression is also essential for enabling the recovery of high concentrations of albumin in the fluid phase.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Albúmina Sérica
/
Receptores de Superficie Celular
/
Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad
/
Albuminuria
/
Túbulos Renales Proximales
/
Nefrosis
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Am J Physiol Renal Physiol
Asunto de la revista:
FISIOLOGIA
/
NEFROLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Estados Unidos