Pseudoaldosteronism and the epithelial sodium channel

Sodium reabsorption in the distal nephron is mediated by the epithelial sodium channel (ENaC). Genetic defects in the regulation of ENaC activity cause two syndromes of mineralocorticoid-independent, salt-sensitive hypertension. Liddle’s syndrome results from mutations in the regulatory subunits of the ENaC, which lead to constitutive activation of this channel. The syndrome of apparent mineralocorticoid excess results from deleterious mutations in the gene encoding 11-hydroxysteroid dehydrogenase type 2. This enzyme protects the mineralocorticoid receptor from spurious activation by glucocorticoids; loss of 11-hydroxysteroid dehydrogenase type 2 activity allows glucocorticoids to activate the receptor and thus increase ENaC activity. The genes involved in these syndromes are candidate loci for increased risk for essential hypertension in humans.