2. Academic Validation
  3. Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting

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

  • JCI Insight. 2021 Jun 22;6(12):e142838. doi: 10.1172/jci.insight.142838.
Rui Wang 1,  Shi-Ting Wu 1,  Xi Yang 1,  Yude Qian 1,  Jaesung P Choi 2,  Rui Gao 1,  Siliang Song 1,  Yixuan Wang 1,  Tao Zhuang 3,  Justin Jl Wong 4,  Yuzhen Zhang 3,  Zhiming Han 5,  Hua A Lu 6,  Stephen I Alexander 7,  Renjing Liu 8,  Yin Xia 9,  Xiangjian Zheng 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China.
  • 2 Lab of Cardiovascular Signaling, Centenary Institute, and Sydney Medical School, University of Sydney, Sydney, Australia.
  • 3 Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4 Epigenetics and RNA Biology Program Centenary Institute and Sydney Medical School, University of Sydney, Sydney, Australia.
  • 5 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
  • 6 Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • 7 Department of Pediatric Nephrology, The Children's Hospital at Westmead and Centre for Kidney Research, Sydney Medical School, University of Sydney, Sydney, Australia.
  • 8 Vascular Epigenetics Laboratory, Victor Chang Cardiac Research Institute, Sydney, Australia.
  • 9 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
PMID: 34156031 DOI: 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.

Keywords

Epithelial transport of ions and water; Mouse models; Nephrology.

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