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Aberrant glycosylation and localization of polycystin-1 cause polycystic kidney
in an AQP11 knockout model
#MMPMID24854278
Inoue Y
; Sohara E
; Kobayashi K
; Chiga M
; Rai T
; Ishibashi K
; Horie S
; Su X
; Zhou J
; Sasaki S
; Uchida S
J Am Soc Nephrol
2014[Dec]; 25
(12
): 2789-99
PMID24854278
show ga
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.
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