Pathogenic Relationships in Cystic Fibrosis and Renal Diseases: CFTR, SLC26A9 and Anoctamins

Abstract

The Cl−-transporting proteins CFTR, SLC26A9, and anoctamin (ANO1; ANO6) appear to have more in common than initially suspected, as they all participate in the pathogenic process and clinical outcomes of airway and renal diseases. In the present review, we will therefore concentrate on recent findings concerning electrolyte transport in the airways and kidneys, and the role of CFTR, SLC26A9, and the anoctamins ANO1 and ANO6. Special emphasis will be placed on cystic fibrosis and asthma, as well as renal alkalosis and polycystic kidney disease. In essence, we will summarize recent evidence indicating that CFTR is the only relevant secretory Cl− channel in airways under basal (nonstimulated) conditions and after stimulation by secretagogues. Information is provided on the expressions of ANO1 and ANO6, which are important for the correct expression and function of CFTR. In addition, there is evidence that the Cl− transporter SLC26A9 expressed in the airways may have a reabsorptive rather than a Cl−-secretory function. In the renal collecting ducts, bicarbonate secretion occurs through a synergistic action of CFTR and the Cl−/HCO3− transporter SLC26A4 (pendrin), which is probably supported by ANO1. Finally, in autosomal dominant polycystic kidney disease (ADPKD), the secretory function of CFTR in renal cyst formation may have been overestimated, whereas ANO1 and ANO6 have now been shown to be crucial in ADPKD and therefore represent new pharmacological targets for the treatment of polycystic kidney disease.

Mechanisms and physiological relevance of acid-base exchange in functional units of the kidney

“…Anoctamins ANO1/6 are required for proper expression and function of CFTR. Thus, in renal collecting system, bicarbonate secretion occurs through a synergistic action of CFTR and pendrin supported by ANO ( Kunzelmann et al, 2023 ). Anion exchanger 4 (AE4), also implicated in bicarbonate transport, is specifically expressed at the basolateral membrane of IC-β.…”

“…Cystic fibrosis is an inherited condition resulting from mutations in CFTR affect bicarbonate secretion in the cortical collecting system as a part of cystic fibrosis phenotype. The dysregulated bicarbonate excretion by the kidneys may result in systemic metabolic alkalosis ( Kunzelmann et al, 2023 ). The Ca 2+ -activated Cl − channel TMEM16A and aquaporin 2 play central roles in the autosomal dominant polycystic kidney disease (ADPKD) ( Talbi et al, 2021 ; Olesen & Fenton, 2021 ).…”

Chloride/Multiple Anion Exchanger SLC26A Family: Systemic Roles of SLC26A4 in Various Organs

“…Overexpression of SLC26A9 increases the current in a CFTR-mutated (∆F508, deletion of phenylalanine) HBE cell line (CFBE41o) [118]. Because ∆F508 CFTR represents CF, SLC26A9 has been suggested as a therapeutic target for CF [126,127]. Additionally, SLC26A9 is associated with asthma and lung inflammation.…”