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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Am+Soc+Nephrol 2014 ; 25 (12): 2789-99 Nephropedia Template TP
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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 PMID24854278show 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 (TgAQP11) that express 3×HA-tagged AQP11 protein were generated. This AQP11 localized to the endoplasmic reticulum (ER) of proximal tubule cells in TgAQP11 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.