Glycogen synthase kinase 3α regulates urine concentrating mechanism in mice

In mammals, glycogen synthase kinase (GSK)3 comprises GSK3 alpha and GSK3 alpha isoforms. GSK3 alpha has been shown to play a role in the ability of kidneys to concentrate urine by regulating vasopressin-mediated water permeability of collecting ducts, whereas the role of GSK3 alpha has yet to be discerned. To investigate the role of GSK3 alpha in urine concentration, we compared GSK3 alpha knockout (GSK3 alpha KO) mice with wild-type (WT) littermates. Under normal conditions, GSK3 alpha KO mice had higher water intake and urine output. GSK3 alpha KO mice also showed reduced urine osmolality and aquaporin-2 levels but higher urinary vasopressin. When water deprived, they failed to concentrate their urine to the same level as WT littermates. The addition of 1-desamino-8-D-arginine vasopressin to isolated inner medullary collecting ducts increased the cAMP response in WT mice, but this response was reduced in GSK3 alpha KO mice, suggesting reduced responsiveness to vasopressin. Gene silencing of GSK3 alpha in mpkCCD cells also reduced forskolin-induced aquaporin-2 expression. When treated with LiCl, an isoform nonselective inhibitor of GSK3 and known inducer of polyuria, WT mice developed significant polyuria within 6 days. However, in GSK3 alpha KO mice, the polyuric response was markedly reduced. This study demonstrates, for the first time, that GSK3 alpha could play a crucial role in renal urine concentration and suggest that GSK3 alpha might be one of the initial targets of Li+ in LiCl-induced nephrogenic diabetes insipidus.