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Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting
Rui Wang1, Shi-Ting Wu1, Xi Yang1
1Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China.
JCI Insight
|June 22, 2021
Summary
The PDCD10-STK-ERM pathway is crucial for kidney water balance. Disrupting this pathway impairs aquaporin 2 function, leading to water reabsorption defects and polyuria.
Area of Science:
- Molecular Biology
- Physiology
- Cell Biology
Background:
- PDCD10 (CCM3) is linked to cerebral cavernous malformations and maintains epithelial integrity.
- PDCD10 forms complexes with GCKIII kinases (STK24, STK25, MST4).
- Previous studies highlight the PDCD10-GCKIII complex's role in epithelial integrity.
Purpose of the Study:
- To investigate the role of the PDCD10-STK pathway in kidney water balance.
- To elucidate the molecular mechanisms underlying water reabsorption defects in PDCD10-deficient mice.
Main Methods:
- Generation of kidney tubule-specific Pdcd10 or Stk24/25 deficient mice.
- Analysis of aquaporin 2 (Aqp2) protein levels and localization.
- Assessment of Ezrin, Radixin, Moesin (ERM) protein expression and phosphorylation.
- Evaluation of intracellular vesicle trafficking.
- Treatment with Erlotinib to assess rescue effects.
Main Results:
- Pdcd10- and Stk24/25-deficient mice exhibited polyuria and increased water consumption.
- Reduced total and phosphorylated Aqp2 protein at the apical membrane despite normal aquaporin gene expression.
- Increased expression and membrane targeting of p-ERM proteins.
- Impaired intracellular vesicle trafficking.
- Erlotinib treatment partially rescued Aqp2 levels and water reabsorption.
Conclusions:
- The PDCD10-STK-ERM signaling pathway regulates kidney water balance.
- This pathway controls AQP2 protein abundance and vesicle trafficking.
- Identification of a novel pathway for controlling water balance in the kidneys.
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