Epithelial sodium channels and hypertension.

Hypertension is a major risk factor for heart attacks, stroke, and kidney failure. It is estimated to cause as many as 25% of all deaths in the United States, particularly for African Americans, in whom the disease is both more common and more severe. Essential hypertension is a multifactorial disorder influenced by both genetic and environmental factors. Physiological studies have shown that the kidneys play an important role in the maintenance of sodium balance, extracellular fluid volume, and long-term control of blood pressure. The sodium transporters in the kidney affect the amount of sodium and water reabsorption in the nephron and thus control extracellular fluid volume and blood pressure. Of the renal sodium transporters, the amiloride-sensitive epithelial sodium channels (ENaC), which are responsible for the rate-limiting step of sodium reabsorption in the distal nephron, are therefore important candidates in the development of hypertension. Moreover, mutations in this channel have been shown to cause a rare form of heritable hypertension (Liddle's syndrome), and genetic linkage studies show that the beta- and gamma-subunits are linked to systolic blood pressure. Several polymorphisms have been identified in the beta- and gamma-subunits of this channel, of which the beta-T594M variant is of particular interest. This variant is found in individuals of African American descent and not in Caucasians and may be associated with hypertension in some populations of African descent. Lymphocytes from individuals with this variant channel show an increased sodium conductance in response to cAMP in vitro. Studying the polymorphic variants in the various subunits of ENaC may further our understanding of the mechanisms that underlie sodium balance in mammals. These variants will provide an avenue to identify molecular targets for new diagnostic and therapeutic tools in the clinical treatment of hypertension.