AE4-dependent signaling in renal ß-intercalated cells

• Applicant: Dr. Helga Vitzthum
• Subject Area: Anatomy and Physiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568384453

The project focuses on renal β-intercalated cells (β-ICs), which play an important role in systemic acid-base homeostasis. The β-ICs are unique as they are the only cells in the kidney that can actively secrete base (HCO3-) into the urine. The extent of base secretion by β-ICs is regulated by altering the activity of the Cl-/HCO3- exchanger Pendrin (SLC26A4). How the activity of Pendrin is controlled is not fully understood. However, we have shown that the transporter AE4 (SLC4A9) is an essential component of the acid-base sensor that enables β-ICs to adapt Pendrin activity to a systemic acid-base disturbance. The aim of this project is to unravel the AE4-dependent intracellular signaling pathway and to identify novel AE4-dependent key players that regulate the activity of β-ICs. To this end, mouse models such as AE4-deficient mice and FRET-based cAMP or Cl- sensor mice will be used. Using various molecular, biochemical and immunohistochemical methods (e.g. spatial transcriptomics, quantitative proteomics, Western blotting, multiplex immunohistochemistry), we will reveal the time- and AE4-dependent changes in the renal transcriptome and proteome upon acid-base imbalance. To elucidate the role of both, the HCO3-/soluble adenylate cyclase (sAC)/cAMP and the Cl-/WNK signalling pathway, we will analyse intracellular [cAMP] and [Cl-] upon base and acid challenge in different model systems, including microdissected cortical collecting ducts and acute kidney slices culture. In addition, the effect of alkali or acid loading on the abundance and subcellular localisation of sAC, phosphodiesterases (PDEs) and WNK bodies will be determined by Western blotting and multiplex immunohistochemistry. The research project will elucidate the intracellular signaling pathway and protein-protein interaction network that regulate Pendrin activity in β-ICs, providing the opportunity to identify new molecular targets for therapeutic intervention.  

• DFG Programme: Research Grants