Kidney Week

Abstract: TH-PO309

The AE4 (Slc4a9) Transporter Is Essential for Renal Acid-Base Sensing

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

• 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic

Authors

• Vitzthum, Helga, Universitatsklinikum Hamburg-Eppendorf Zentrum fur Experimentelle Medizin, Hamburg, Hamburg, Germany

Helga Vitzthum,

• Koch, Mirijam, Universitatsklinikum Hamburg-Eppendorf Zentrum fur Experimentelle Medizin, Hamburg, Hamburg, Germany

Mirijam Koch,

• Eckermann, Leya, Universitatsklinikum Hamburg-Eppendorf Zentrum fur Experimentelle Medizin, Hamburg, Hamburg, Germany

Leya Eckermann,

• Svendsen, Samuel L.C., Aarhus University, Department of Biomedicine, Aarhus, Midtjylland, Denmark

Samuel L.C. Svendsen,

• Berg, Peder, Aarhus University, Department of Biomedicine, Aarhus, Midtjylland, Denmark

Peder Berg,

• Dreger, Kimberley, Universitatsklinikum Hamburg-Eppendorf Zentrum fur Experimentelle Medizin, Hamburg, Hamburg, Germany

Kimberley Dreger,

• Hübner, Christian A., University Hospital Jena Institute of Human Genetics, Jena, Thüringen, Germany

Christian A. Hübner,

• Wagner, Carsten A., University of Zurich and National Center of Competence in Research NCCR Kidney, Zurich, ZH, Switzerland

Carsten A. Wagner,

• Leipziger, Jens G., Aarhus University, Department of Biomedicine, Aarhus, Midtjylland, Denmark

Jens G. Leipziger,

• Meyer-Schwesinger, Catherine, Universitatsklinikum Hamburg-Eppendorf Zentrum fur Experimentelle Medizin, Hamburg, Hamburg, Germany

Catherine Meyer-Schwesinger,

• Ehmke, Heimo, Universitatsklinikum Hamburg-Eppendorf Zentrum fur Experimentelle Medizin, Hamburg, Hamburg, Germany

Heimo Ehmke,

Background

Renal acid (H⁺) and base (HCO₃^-) secretion into the urine rapidly change upon systemic acid-base imbalances. Central for this task are specialized cells in the distal nephron, the α- and β-intercalated cells (ICs). How these cells sense acid-base disturbances is a long-standing question. Interestingly, the base secreting β-ICs almost exclusively express the Na⁺-dependent Cl^-/HCO₃^- exchanger AE4 (Slc4a9). AE4 is considered to play an important role in the maintenance of salt-water balance. This proposed function could not be confirmed in our analyses of AE4 knockout mice. Here we analyzed whether the AE4 is involved in the regulation of pendrin-dependent HCO₃^- secretion in β-ICs upon base or acid loading.

Methods

Ae4 knockout mice (Slc4a9^-/-) and wild-type littermates (Slc4a9^+/+) received a normal or salt deficient diet for up to 7 days combined with an oral alkali or acid loading. The acid-base status, renal abundance and subcellular distribution of pendrin and Ae4, and activity of pendrin were analyzed.

Results

Wild-type mice elicited a proper response to alkali loading, characterized by an increase of pendrin mRNA and protein abundance, a shift of pendrin to the apical membrane, an enhanced pendrin activity in ß-ICs, and an elevated urinary HCO₃^- excretion. Upon acid loading both, Ae4 and pendrin abundance were reduced in wild-type mice. In contrast, AE4 knockout mice failed to initiate any change of pendrin abundance or subcellular distribution upon base or acid loading. The failure to adapt pendrin activity and urinary HCO₃^- secretion upon base loading culminated in severe metabolic alkalosis under salt restricted conditions.

Conclusion

The basolateral transporter AE4 is an essential part of the renal sensing mechanism for changes in acid-base status, and an insufficient function of AE4 precludes the proper reaction of ß-ICs to alkalosis or acidosis.