The association between diabetes insipidus (DI) and chronic dietary potassium deprivation is well known but it remains uncertain how the disorder develops and whether it is influenced by the sexual dimorphism in potassium handling. Here, we determine the plasma potassium (PK) threshold for DI in male and female mice and ascertain if the DI is initiated by polydipsia, or a central or nephrogenic defect. C57BL6J mice were randomized to a control diet or to graded reductions in dietary K+ for 8 days, and kidney function and transporters involved in water balance were characterized. We found male and female mice develop polyuria and secondary polydipsia. Altered water balance coincides with a decrease in AQP2 phosphorylation and apical localization despite increased levels of the vasopressin surrogate marker, copeptin. No change in the protein abundance of the urea transporter, UT-A1, was observed. NKCC2 decreased only in males. DDAVP treatment failed to reverse water diuresis in K+-restricted mice. These findings indicate that even small fall in PK is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low PK as a causal trigger of NDI. We found PK decreased more in females, and consequently females were more prone to develop NDI. Together these data indicate that AQP2 regulation is disrupted by a small decrease in PK and the response is influenced by sexual dimorphism in potassium handling. These findings provide new insights into the mechanisms linking water and potassium balances, and support defining the disorder as "Potassium-Dependent NDI."
Keywords: AQP2; Cellular Remodeling; Potassium; Sexual Dimorphism; Vasopressin Resistance.