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Aquaporin‐1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling
Author(s) -
Wang Weiling,
Li Fei,
Sun Yi,
Lei Lei,
Zhou Hong,
Lei Tianluo,
Xia Yin,
Verkman A. S.,
Yang Baoxue
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-260828
Subject(s) - wnt signaling pathway , aquaporin 1 , polycystic kidney disease , kidney , aquaporin 2 , signal transduction , biology , endocrinology , medicine , microbiology and biotechnology , kidney development , cancer research , biochemistry , water channel , mechanical engineering , embryonic stem cell , gene , engineering , inlet
Water channel aquaporin‐1 (AQP1) is expressed at epithelial cell plasma membranes in renal proximal tubules and thin descending limb of Henle. Recently, AQP1 was reported to interact with β‐catenin. Here we investigated the relationship between AQP1 and Wnt signaling in in vitro and in vivo models of autosomal dominant polycystic kidney disease (PKD). AQP1 overexpression decreased β‐catenin and cyclinD1 expression, suggesting down‐regulation of Wnt signaling, and coimmunoprecipitation showed AQP1 interaction with β‐catenin, glycogen synthase kinase 3β, LRP6, and Axin1. AQP1 inhibited cyst development and promoted branching in matrix‐grown MDCK cells. In embryonic kidney cultures, AQP1 deletion increased cyst development by up to ~40%. Kidney size and cyst number were significantly greater in AQP1‐null PKD mice than in AQP1‐expressing PKD mice, with the difference mainly attributed to a greater number of proximal tubule cysts. Biochemical analysis revealed decreased β‐catenin phosphorylation and increased β‐catenin expression in AQP1‐null PKD mice, suggesting enhanced Wnt signaling. These results implicate AQP1 as a novel determinant in renal cyst development that may involve inhibition of Wnt signaling by an AQP1‐macromolecular signaling complex.—Wang, W., Li, F., Sun, Y., Lei, L., Zhou, H., Lei, T., Xia, Y., Verkman, A. S., Yang, B. Aquaporin‐1 retards renal cyst development in polycystic kidney disease by inhibition of Wnt signaling. FASEB J. 29, 1551‐1563 (2015). www.fasebj.org