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 (AC6^{loxloxPax8Cre}). 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, AC6^{loxloxPax8Cre} 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.