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
  • 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.
Products