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.

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