Secondary hyperparathyroidism and impaired renal phosphate excretion in mice lacking adenylyl cyclase 6

Abstract

Parathyroid hormone (PTH) activates an unidentified isoform of adenylyl cyclase (AC) thereby retrieving Na+/phosphate cotransporters from the proximal tubule membrane and increasing phosphate (Pi) excretion. Fibroblast growth factor (FGF) 23 is a novel AC‐independent phosphaturic hormone. To test for a role of AC6 we studied wild‐type (WT, n=10) and AC6 knockout (AC6−/−, n=9) mice under different Pi intake (low: <0.02% Pi; control: 0.6% Pi; both 0.8% Ca2+). Plasma Pi was similar on control diet (both 1.6±0.1 mM) but AC6−/− had lower urinary Pi/creatinine (Crea) (7±1 vs 17±1 mM/mM, P<0.05) despite of higher plasma PTH and FGF23 vs WT (1057±223 vs 140±23 and 923±124 vs. 629±119 pg/ml, P<0.05). Low Pi intake (7 days) suppressed PTH (11±5 and 7±7 pg/ml); despite of higher FGF23 (629±119 vs 302±78 pg/ml, P<0.05) AC6−/− had lower urinary Pi/Crea (0.09±0.01 vs 0.13±0.01 mM/mM, P<0.05) and maintained higher plasma Pi vs WT (1.3±0.1 vs 0.9±0.1 mM, P<0.05). Acute oral phosphate loading (0.5 M NaH2PO4, 1% of bw) under low Pi diet induced higher plasma Pi in AC6−/− vs WT (Δ change 30 min: 1.3±0.2 vs 0.8±0.1 mM; 60 min: 2.1±0.3 vs 1.4±0.2 mM, P<0.05) but urinary Pi/Crea tended to be lower in AC6−/− (60 min: 35±14 vs 63±16 mM/mM). Dissociation of PTH and urinary Pi excretion in AC6−/− is consistent with AC6 mediating PTH‐induced inhibition of renal Pi reabsorption, while upregulation of FGF23 may compensate.