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.
Highlights
Water homeostasis is critical for all physiological processes, and water channel–mediated reabsorption by the kidney is essential to maintain the body’s water balance
Urine production, and urine osmolality were not altered between these Krit1- or Ccm2-deficient mice and their littermate controls (Supplemental Figure 4). These results indicate that the regulation of body water balance is not a general function of cerebral cavernous malformations (CCMs) complex proteins — rather, this function is unique to Pdcd10
Dysfunctional targeting of AQP2 to the epithelial cell membrane is an immediate cause of nephrogenic diabetes insipidus (NDI)
Summary
Water homeostasis is critical for all physiological processes, and water channel–mediated reabsorption by the kidney is essential to maintain the body’s water balance. The kidneys express numerous aquaporins (AQP) where AQP1–4 and AQP7 are the major AQP involved in water handling. The localization of AQP2 on the luminal membrane is a key regulatory node for water absorption by the kidney tubules. The hypothalamus senses osmolality to secrete arginine vasopressin (AVP), and AVP interacts with vasopressin V2 receptor (V2R) in kidney epithelial cells to stimulate AQP2 phosphorylation and promote its translocation to the luminal membrane [4]. The AVP-V2R-AQP2 axis is the major regulatory pathway for water reabsorption in the mammalian body
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