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Abstract: TH-PO363

Manganese Promotes Intracellular Accumulation of AQP2 via Modulating F-Actin Polymerization and Reduces Urinary Concentration in Mice

Session Information

Category: Cell Biology

  • 201 Cell Signaling, Oxidative Stress


  • Huang, Ming, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Lei, Lei, Massachusetts General Hospital, Boston, United States
  • Paunescu, Teodor G., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Yang, Baoxue, School of Basic Medical Sciences, Peking University, Beijing, China
  • Lu, Hua Ann Jenny, Massachusetts General Hospital, Boston, Massachusetts, United States

Aquaporin-2 (AQP2) is a water channel protein expressed in principal cells (PCs) of the kidney collecting ducts (CDs) and plays a critical role in urine concentration. F-actin polymerization through Rho phosphorylation is one of the key determinants for the cytoskeletal dynamics controlling AQP2 trafficking. Preliminary studies have shown that manganese stabilizes F-actin nuclei and decreases the concentration of its monomers at the steady state. We report in this study that manganese chloride (MnCl2) is a novel and potent regulator of AQP2 trafficking in cells and in the kidney. We observed aperinuclear accumulation of AQP2 in both cultured cells and kidney CDs in response to MnCl2 treatment. This effect of MnCl2 on AQP2 distribution was associated with an increase in the rate of AQP2 endocytosis without alteration of the overall exocytosis. This perinuclear accumulation of AQP2 induced by MnCl2 was resistant to vasopressin (VP) simulation. Although the level of total and phosphorylated AQP2 did not change, MnCl2 treatment impeded VP-induced phosphorylation of AQP2 at its serine residues 256, 264, 269 and dephosphorylation at serine 261. In addition, MnCl2 significantly promoted F-actin polymerization along with downregulation of RhoA activity, and prevented VP-induced AQP2 membrane accumulation. Finally, MnCl2 treatment caused significant polyuria and reduced urinary concentration in mice, likely by promoting intracellular accumulation of AQP2. More importantly, this reduced urinary concentration induced by MnCl2 was resistant to VP treatment. In summary, our study identified a novel effect of MnCl2 on AQP2 trafficking, and proved its potent impact on regulating urinary concentration in animals.