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Aquaporin-11 knockout mice and polycystic kidney disease animals share a common mechanism of cyst formation

Shinji Okada^*, Takumi Misaka^*, Yasuko Tanaka, Ichiro Matsumoto^*, Kenichi Ishibashi, Sei Sasaki and Keiko Abe^*,1

^* Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan;

Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan; and

Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan

¹Correspondence: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. E-mail: aka7308{at}mail.ecc.u-tokyo.ac.jp

Aquaporin-11 (AQP11), a new member of the aquaporin family, is localized in the endoplasmic reticulum (ER). Aqp11^–/– mice neonatally suffer from polycystic kidneys derived from the proximal tubule. Its onset is proceeded by the vacuolization of ER. However, the mechanism for the formation of vacuoles and cysts remains to be clarified. Here, we show that Aqp11^–/– mice and polycystic kidney disease (PKD) animals share a common pathogenic mechanism of cyst formation. We performed microarray analyses and histochemical staining to characterize the effects of the disruption of Aqp11 on kidneys of 1-wk-old mice. Microarray analyses revealed that the significantly changed functional categories in Aqp11^–/– mice were similar to those in PKD animals. Histochemical studies showed expression changes of 3 genes, Myc, Egfr, Egf, which are assumed to be involved in the proliferation of cystic cells in PKD. We actually confirmed the activation of cell proliferation in the proximal tubule cells with vacuolized ER. Furthermore, three genes associated with the remodeling of the extracellular matrix, Mmp12, Timp1, Tgfb1, were up-regulated in the fibroblasts. We also demonstrated the activation of apoptosis via the ER-stress pathway in the proximal tubule cells with vacuolized ER. These results provide new insights into the physiological roles of AQP11.—Okada, S., Misaka, T., Tanaka, Y., Matsumoto, I., Ishibashi, K., Sasaki, S., Abe, K. Aquaporin-11 knockout mice and polycystic kidney disease animals share a common mechanism of cyst formation.

Key Words: subcellular aquaporin • DNA microarray • histochemical analysis • ER stress