GSK3β Mediates Renal Response to Vasopressin by Modulating Adenylate Cyclase Activity

Glycogen synthase kinase 3 beta (GSK3 beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3 beta, causes nephrogenic diabetes insipidus, GSK3 beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3 beta knockout mice to determine whether deletion of GSK3 beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3 beta gene deletion and pharmacologic inhibition of GSK3 beta reduced adenylate cyclase activity. In summary, GSK3 beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.