Salt sensitivity of volume and blood pressure in a mouse with globally reduced ENaC γ-subunit expression

The epithelial Na⁺ channel (ENaC) promotes the absorption of Na⁺ in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding subunits of ENaC results in early postnatal mortality. Here, we present the initial characterization of a mouse with dramatically suppressed expression of the ENaC γ-subunit. We used this hypomorphic (γ^mt) allele to explore the importance of this subunit in homeostasis of electrolytes and body fluid volume. At baseline, γ-subunit expression in γ^mt/mt mice was markedly suppressed in the kidney and lung, whereas electrolytes resembled those of littermate controls. Aldosterone levels in γ^mt/mt mice exceeded those seen in littermate controls. Quantitative magnetic resonance measurement of body composition revealed similar baseline body water, lean tissue mass, and fat tissue mass in γ^mt/mt mice and controls. γ^mt/mt mice exhibited a more rapid decline in body water and lean tissue mass in response to a low-Na⁺ diet than the controls. Replacement of drinking water with 2% saline selectively and transiently increased body water and lean tissue mass in γ^mt/mt mice relative to the controls. Lower blood pressures were variably observed in γ^mt/mt mice on a high-salt diet compared with the controls. γ^mt/mt also exhibited reduced diurnal blood pressure variation, a "nondipping" phenotype, on a high-Na⁺ diet. Although ENaC in the renal tubules and colon works to prevent extracellular fluid volume depletion, our observations suggest that ENaC in other tissues may participate in regulating extracellular fluid volume and blood pressure.NEW & NOTEWORTHY A mouse with globally suppressed expression of the epithelial Na⁺ channel γ-subunit showed enhanced sensitivity to dietary salt, including a transient increase in total body fluid, reduced blood pressure, and reduced diurnal blood pressure variation when given a dietary NaCl challenge. These results point to a role for the epithelial Na⁺ channel in regulating body fluid and blood pressure beyond classical transepithelial Na⁺ transport mechanisms.