Compensatory up-regulation of angiotensin II subtype 1 receptors in alpha ENaC knockout heterozygous mice

Background. In mice, a partial loss of function of the epithelial sodium ch annel (ENaC), which regulates sodium excretion in the distal nephron, cause s pseudohypoaldosteronism, a salt-wasting syndrome. The purpose of the pres ent experiments was to examine how alpha ENaC knockout heterozygous (+/-) m ice, which have only one allele of the gene encoding for the a subunit of E NaC, control their blood pressure (BP) and sodium balance. Methods. BP, urinary electrolyte excretion, plasma renin activity, and urin ary adosterone were measured in wild-type (+/+) and heterozygous (+/-) mice on a low, regular, or high sodium diet. In addition, the BP response to an giotensin II (Ang II) and to Ang II receptor blockade, and the number and a ffinity of Ang II subtype 1 (AT(1)) receptors in renal tissue were analyzed in both mouse strains on the three diets. Results. In comparison with wild-type mice (+/+), alpha ENaC heterozygous m utant mice (+/-) showed an intact capacity to maintain BP and sodium balanc e when studied on different sodium diets. However, no change in plasma reni n activity was found in response to changes in sodium intake in alpha ENaC +/- mice. On a normal salt diet, heterozygous mice had an increased vascula r responsiveness to exogenous Ang II (P < 0.01). Moreover, on a normal and low sodium intake, these mice exhibited an increase in the number of AT(1) receptors in renal tissues; their BP lowered markedly during the Ang II rec eptor blockade (P < 0.01) and there was a clear tendency for an increase in urinary aldosterone excretion. Conclusions. alpha ENaC heterozygous mice have developed an unusual mechani sm of compensation leading to an activation of the renin-angiotensin system , that is, the up-regulation of AT(1) receptors. This up-regulation may be due to an increase in aldosterone production.