Goreisan promotes diuresis by regulating the abundance of aquaporin 2 phosphorylated at serine 269 through calcium-sensing receptor activation

Aquaporin 2 (AQP2) contributes to water reabsorption and urine concentration by migrating to the luminal surface of the collecting ducts in an anti-diuretic hormone-stimulated manner, and the signaling pathway involved in AQP2 subcellular localization is a target for arginine vasopressin receptor antagonists (aquaretics). This study investigated the involvement of AQP2 in the diuretic effect and mechanisms of Goreisan (GRS), a traditional Japanese Kampo medicine used to treat conditions such as edema in patients with decreased urination. GRS exerted diuretic effects on desmopressin (DDAVP)-induced decreases in urine output and the level of AQP2 phosphorylated at Serine269 (pSer269-AQP2) in the renal tissues of mice. Furthermore, GRS inhibited the accumulation of pSer269-AQP2 to the luminal side following forskolin stimulation using a 3D culture model of the kidney collecting duct cell line mIMCD-3. GRS induced a transient increase in the intracellular Ca²⁺ concentration via the calcium-sensing receptor (CaSR) and suppressed the forskolin-stimulated increase in cAMP production. These results suggest that GRS regulates urine volume by modulating the subcellular localization of AQP2 via CaSR.