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Renal Collecting Duct GSK3ß Deletion Affects Response To AVP By Reducing Adenylate Cyclase Activity
Author(s) -
Rao Reena,
Patel Satish,
Woodgett Jim,
Matthew Breyer,
Raymond Harris
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.1001.6
Subject(s) - medicine , endocrinology , aquaporin 2 , reabsorption , forskolin , urine osmolality , gsk 3 , adenylate kinase , vasopressin , chemistry , kidney , biology , kinase , biochemistry , stimulation , receptor , water channel , mechanical engineering , engineering , inlet
Glycogen synthase kinase 3 (GSK3) is potently inhibited by lithium, a common treatment for bipolar disorders, which impairs urinary concentrating ability in 20‐30% of patients. To examine if GSK3ß is crucial for regulating vasopressin (AVP) dependent water reabsorption in the renal collecting duct (CD), we developed CD specific GSK3ß knockout mice (GSK3ß‐CD null). These mice had lower urine osmolality, renal aquaporin 2 (AQP2) mRNA and protein levels following water deprivation or dDAVP treatment, compared to wild type (WT) mice. dDAVP and forskolin induced cAMP generation was lower in the GSK3ß‐CD null mice and GSK3ß inhibitor treated WT mice or IMCD cells. We measured the renal AC activity in membrane preparation from WT and GSK3ß ‐CD null mice. dDAVP or forskolin induced AC activity in GSK3ß‐CD null group was reduced by up to 50% and 40% respectively compared to the WT group. Over 68% suppression of AC activity was observed in WT membranes treated with SB216763. These studies show for the first time that GSK3ß inhibition or deletion leads to lower cAMP generation due to reduced AC activity, which could be responsible for low AQP2 expression and impaired response to AVP in the GSK3ß‐CD null mice.