Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting

Wang, Rui and Wu, Shi-Ting and Yang, Xi and Qian, Yude and Choi, Jaesung P. and Gao, Rui and Song, Siliang and Wang, Yixuan and Zhuang, Tao and Wong, Justin J.L. and Zhang, Yuzhen and Han, Zhiming and Lu, Hua A. and Alexander, Stephen I. and Liu, Renjing and Xia, Yin and Zheng, Xiangjian (2021) Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting. JCI Insight, 6 (12). ISSN 2379-3708

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Link to published document: http://doi.org/10.1172/jci.insight.142838

Abstract

PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 31 Jul 2021 06:09
Last Modified: 01 Aug 2021 04:37
URI: http://eprints.victorchang.edu.au/id/eprint/1108

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