Collecting Duct‐Specific Knockout of Adenylyl Cyclase Type VI Causes Urinary Concentration Defect in Mice

Abstract

Adenylyl cyclase VI (AC6) has been implicated in arginine vasopressin (AVP)‐stimulated renal water reabsorption. To evaluate the AC6 role we generated mice with collecting duct (CD)‐specific KO of AC6 using the Cre/lox system. KO and floxed controls were studied on normal water, chronically water loaded, and water deprived for 18 hours, ± DDAVP clamp 25ng/hr. Food, water intake, body weight, urine volume and osmolality, and inner medullary collecting duct (IMCD) AVP stimulated cAMP levels were measured. Baseline urine osmolality (Uosm) was reduced (1427±91 KO vs. 1938±189 mOsm/L con, p<0.04). After 18 hr water deprivation, Uosm was also reduced (2271±160 KO vs. 2777±108 mOsm/L con, p<0.02). There was no change with chronic water loading. With DDAVP infusion there was no difference in Uosm with normal conditions, or chronic water loading. With water deprivation Uosm decreased (3142±50 KO vs 3332±63 mOsm/L con p=0.032). There was no difference in urine volume or fluid intake. In acutely isolated IMCD AVP stimulated cAMP accumulation was reduced (0.09±0.015 KO vs. 0.16±0.015 pmol/μg con p=0.016). Thus, AC6 plays an important role in AVP stimulated water reabsorption and cAMP accumulation in CD.