Aberrant glycosylation and localization of polycystin-1 cause polycystic kidney in an AQP11 knockout model.
J Am Soc Nephrol
; 25(12): 2789-99, 2014 Dec.
Article
em En
| MEDLINE
| ID: mdl-24854278
ABSTRACT
We previously reported that disruption of the aquaporin-11 (AQP11) gene in mice resulted in cystogenesis in the kidney. In this study, we aimed to clarify the mechanism of cystogenesis in AQP11(-/-) mice. To enable the analyses of AQP11 at the protein level in vivo, AQP11 BAC transgenic mice (Tg(AQP11)) that express 3×HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in Tg(AQP11) mice and rescued renal cystogenesis in AQP11(-/-) mice. Therefore, we hypothesized that the absence of AQP11 in the ER could result in impaired quality control and aberrant trafficking of polycystin-1 (PC-1) and polycystin-2 (PC-2). Compared with kidneys of wild-type mice, AQP11(-/-) kidneys exhibited increased protein expression levels of PC-1 and decreased protein expression levels of PC-2. Moreover, PC-1 isolated from AQP11(-/-) mice displayed an altered electrophoretic mobility caused by impaired N-glycosylation processing, and density gradient centrifugation of kidney homogenate and in vivo protein biotinylation revealed impaired membrane trafficking of PC-1 in these mice. Finally, we showed that the Pkd1(+/-) background increased the severity of cystogenesis in AQP11(-/-) mouse kidneys, indicating that PC-1 is involved in the mechanism of cystogenesis in AQP11(-/-) mice. Additionally, the primary cilia of proximal tubules were elongated in AQP11(-/-) mice. Taken together, these data show that impaired glycosylation processing and aberrant membrane trafficking of PC-1 in AQP11(-/-) mice could be a key mechanism of cystogenesis in AQP11(-/-) mice.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aquaporinas
/
Canais de Cátion TRPP
/
Doenças Renais Policísticas
Limite:
Animals
Idioma:
En
Revista:
J Am Soc Nephrol
Assunto da revista:
NEFROLOGIA
Ano de publicação:
2014
Tipo de documento:
Article