Why does increased sodium (Na+) reabsorption in cystic fibrosis (CF) cause a more negative transepithelial potential difference?

From the Guidelines

Increased sodium (Na+) reabsorption in cystic fibrosis causes a more negative transepithelial potential difference due to the fundamental defect in chloride (Cl-) transport, as evidenced by the impaired function of the CFTR protein, which normally acts as a chloride channel 1.

Mechanism of Action

The CFTR protein, when functional, regulates epithelial fluid and salt secretion by controlling the movement of chloride ions across the epithelial membrane. In cystic fibrosis, mutations in the CFTR gene, such as the commonly reported F508del mutation, lead to impaired CFTR function, resulting in reduced chloride secretion into the airway lumen.

• Meanwhile, epithelial sodium channels (ENaC) become hyperactive, leading to increased sodium absorption from the airway surface liquid into the epithelial cells.
• This creates an electrochemical imbalance across the epithelium, as positively charged sodium ions are rapidly removed from the airway surface without the compensatory movement of negatively charged chloride ions in the same direction.

Clinical Implications

The airway surface becomes more electronegative relative to the cell interior, resulting in an increased negative potential difference that can be measured across the epithelium and serves as one of the diagnostic features of cystic fibrosis 1.

• The altered ion transport also results in dehydration of airway secretions, contributing to the thick, sticky mucus characteristic of the disease.
• Recent studies have also implicated CFTR in the regulation of insulin secretion from the pancreatic islet, suggesting a potential link between CFTR dysfunction and cystic fibrosis-related diabetes (CFRD) 1.

Key Points

• The impaired function of the CFTR protein leads to reduced chloride secretion and increased sodium absorption, resulting in an electrochemical imbalance across the epithelium.
• The increased negative potential difference can be measured across the epithelium and serves as a diagnostic feature of cystic fibrosis.
• The altered ion transport contributes to the dehydration of airway secretions, resulting in thick, sticky mucus characteristic of the disease.

From the Research

Increased Sodium Reabsorption in Cystic Fibrosis

• Increased sodium (Na+) reabsorption in cystic fibrosis (CF) is associated with a higher Na+ permeability of the apical membrane of airway epithelial cells 2.
• This increase in Na+ permeability is thought to be due to an increase in the open probability of Na(+)-permeable channels in the apical membrane 2.
• The increased Na+ reabsorption in CF is also believed to result from the failure of the cystic fibrosis transmembrane conductance regulator (CFTR) to restrict salt absorption through the epithelial Na+ channel (ENaC) 3.

Mechanism of Increased Sodium Reabsorption

• The mechanism of increased Na+ reabsorption in CF involves an increase in the activity of ENaC, which is not directly related to the defect in CFTR 4, 5.
• CFTR can directly down-regulate single Na+ channel activity, thus accounting for the observed differences in Na+ transport between normal and cystic fibrosis-affected airway epithelia 6.
• The presence of CFTR prohibits the inward rectification of the gating of the renal Na+ channel normally induced by PKA-mediated phosphorylation, thus down-regulating inward Na+ current 6.

Effect on Transepithelial Potential Difference

• The increased Na+ reabsorption in CF leads to a more negative transepithelial potential difference, as the increased Na+ absorption is electrogenic and can alter the electrical properties of the epithelium 2, 5.
• The more negative transepithelial potential difference can have significant effects on the function of the airway epithelium, including altered ion and water transport 5.