Oxidative stress increases aquaporin-2 membrane accumulation in renal epithelial cells and urine osmolality in tolvaptan-induced nephrogenic diabetes insipidus

Reactive oxygen species (ROS) modulate solute and water transport throughout the nephron. In the collecting duct, recycling of the aquaporin-2 (AQP2) water channel to and from the apical membrane is essential for regulating urinary water excretion, yet the role of ROS in AQP2 trafficking remains elusive. Here, we show that the oxidant menadione, a form of vitamin K (K3), induces membrane accumulation of AQP2 by both increasing exocytosis and decreasing endocytosis of AQP2-containing vesicles. K3 induced an AQP2 phosphorylation pattern distinct from that induced by vasopressin (VP), AQP2’s canonical activator, and increased AQP2 plasma membrane accumulation without raising cAMP levels or utilizing PKA. We found that other oxidizing agents, but not other forms of vitamin K, also stimulated AQP2 membrane expression. K3 increased dihydroethidium (DHE) oxidation in LLC-AQP2 cells, and treatment with the reducing agent glutathione completely inhibited the effect of K3 on AQP2 membrane accumulation. Finally, K3 acutely reduced urine output and increased urine osmolality in a rodent model of nephrogenic diabetes insipidus (NDI) induced by the vasopressin receptor (V2R) antagonist tolvaptan. Taken together, our findings show that oxidative stress stimulates AQP2-mediated water reabsorption, suggesting redox regulation of AQP2 may operate as an adaptive response to renal oxidative stress induced by hypovolemia and/or dehydration.