The ENaC channel as the primary determinant of two human diseases: Liddle syndrome and pseudohypoaldosteronism.

The amiloride-sensitive epithelial sodium channel (ENaC) controls sodium reabsorption in the distal nephron. Its activity is under the control of aldosterone. The genes encoding ENaC have been identified and revealed an heteromultimeric structure of the protein composed of three homologous alpha beta gamma subunits. The role of ENaC in the pathogenesis of hypertension has been demonstrated by complete linkage of the gene encoding the beta and gamma subunits to an autosomal form of salt-sensitive hypertension. Analysis of these genes from patients affected by a sever hypertension (Liddle syndrome) identified mutations in the carboxy-terminus of ENaC subunits causing channel hyperactivity, consistent with increased sodium reabsorption in the distal nephron. Pseudohypoaldosteronism type-1 (PHA-1) represents a hereditary form of salt-loosing nephropathy characterized by hyperkalemia, dehydration and metabolic acidosis. Analysis of genes encoding ENaC subunits in patients affected by PHA-1 identified different types of mutations causing loss of function or a decrease in ENaC channel activity. These studies demonstrated the critical role of ENaC channel in the maintenance salt and extracellular fluid balance, and regulation of blood pressure.