Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model

作者：Inoue Yuichi; Sohara Eisei^*; Kobayashi Katsuki; Chiga Motoko; Rai Tatemitsu; Ishibashi Kenichi; Horie Shigeo; Su Xuefeng; Zhou Jing; Sasaki Sei; Uchida Shinichi

来源：Journal of the American Society of Nephrology, 2014, 25(12): 2789-2799.

DOI：10.1681/ASN.2013060614

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 3xHA-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.

• 出版日期2014-12