| First Author | Nørregaard R | Year | 2015 |
| Journal | Am J Physiol Renal Physiol | Volume | 308 |
| Issue | 6 | Pages | F650-60 |
| PubMed ID | 25608967 | Mgi Jnum | J:280213 |
| Mgi Id | MGI:6369146 | Doi | 10.1152/ajprenal.00516.2014 |
| Citation | Norregaard R, et al. (2015) Glycogen synthase kinase 3alpha regulates urine concentrating mechanism in mice. Am J Physiol Renal Physiol 308(6):F650-60 |
| abstractText | In mammals, glycogen synthase kinase (GSK)3 comprises GSK3alpha and GSK3beta isoforms. GSK3beta 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 GSK3alpha has yet to be discerned. To investigate the role of GSK3alpha in urine concentration, we compared GSK3alpha knockout (GSK3alphaKO) mice with wild-type (WT) littermates. Under normal conditions, GSK3alphaKO mice had higher water intake and urine output. GSK3alphaKO 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 GSK3alphaKO mice, suggesting reduced responsiveness to vasopressin. Gene silencing of GSK3alpha 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 GSK3alphaKO mice, the polyuric response was markedly reduced. This study demonstrates, for the first time, that GSK3alpha could play a crucial role in renal urine concentration and suggest that GSK3alpha might be one of the initial targets of Li(+) in LiCl-induced nephrogenic diabetes insipidus. |
