Adenylyl cyclase 6 is required for maintaining acid-base homeostasis.

Adenylyl cyclase (AC) isoform 6 (AC6) is highly expressed throughout the renal tubule and collecting duct (CD), catalyzes the synthesis of cAMP and contributes to various aspects of renal transport. Several proteins involved in acid-base homeostasis are regulated by cAMP. In the present study, we assess the relative contribution of AC6 to overall acid-base regulation using mice with global deletion of AC6 (AC6-/- ) or newly generated mice lacking AC6 in the renal tubule and CD (AC6loxloxPax8Cre ). Higher energy expenditure in AC6-/- relative to wild-type (WT) mice, was associated with lower urinary pH, mild alkalosis in conjunction with elevated blood HCO3 - concentrations, and significantly higher renal abundance of the H+ -ATPase B1 subunit. In contrast with WT mice, AC6-/- mice have a less pronounced increase in urinary pH after 8 days of HCO3 - challenge, which is associated with increased blood pH and HCO3 - concentrations. Immunohistochemistry demonstrated that AC6 was expressed in intercalated cells (IC), but subcellular distribution of the H+ -ATPase B1 subunit, pendrin, and the anion exchangers 1 and 2 in AC6-/- mice was normal. In the AC6-/- mice, H+ -ATPase B1 subunit levels after HCO3 - challenge were greater, which correlated with a higher number of type A IC. In contrast with the AC6-/- mice, AC6loxloxPax8Cre mice had normal urinary pH under baseline conditions but higher blood HCO3 - than controls after HCO3 - challenge. In conclusion, AC6 is required for maintaining normal acid-base homeostasis and energy expenditure. Under baseline conditions, renal AC6 is redundant for acid-base balance but becomes important under alkaline conditions.