PTH‐stimulated urinary phosphate and cAMP excretion are absent in mice lacking adenylyl cyclase 6

Abstract

Parathyroid hormone (PTH) activates an unidentified isoform of adenylyl cyclase (AC) thereby retrieving Na+/Pi cotransporters from the proximal tubule membrane and increasing Pi excretion. To test for a role adenylyl cyclase 6 (AC6) we studied wild‐type (WT, n=8) and AC6 knockout (AC6−/−, n=6) mice in clearance experiments under anesthesia. Bolus application of vehicle (Veh; 0.85% NaCl, 0.5 μl/g bw) or PTH (1, 3, 10, 30 or 100 μg/kg bw) was followed by a 5 min distribution phase and a 15 min quantitative urine collection. After Veh application absolute (AE Pi) as well as fractional urinary Pi excretion (FE Pi) were significantly higher in AC6−/− vs WT mice (4.3±1.2 vs 0.8±0.3 nmol/min/g bw, and 23±6 vs 4±1 %, P<0.05 vs AC6−/−, respectively), and urinary cAMP excretion (AE cAMP) tended to be lower in AC6−/− vs WT mice (0.8±0.2 vs 1.5±0.4 nmol/min/g bw), while glomerular filtration rate was modestly lower in AC6−/− vs WT mice (8.9±1 vs 11.8±1 μl/min/g bw, P<0.05 vs AC6−/−). PTH dose‐dependently increased AE Pi, FE Pi and AE cAMP in WT mice (max responses of 678±205% vs Veh, 23±4%, and 624±136% vs Veh, P<0.05 vs Veh, respectively). In contrast to WT mice, PTH decreased AE Pi (max response −81±3%, P<0.05 vs Veh), did not change FE Pi excretion and AE cAMP (all doses not significant from Veh). Lack of PTH‐induced urinary Pi and cAMP excretion in AC6−/− mice is consistent with AC6 in the proximal tubule mediating these responses.