Water and Electrolyte Homeostasis in a Mouse Model with Reduced ENaC Gamma Subunit Expression

Abstract

The epithelial Na+ channel (ENaC) promotes the absorption of Na+ in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding ENaC’s subunits results in early post-natal mortality. We present initial characterization of a mouse with dramatically suppressed expression of the γ subunit. We use this hypomorphic (γmt) allele to explore the importance of ENaC’s γ subunit in homeostasis of electrolytes and body fluid volume. At baseline, γ subunit expression in γmt/mt mice is markedly suppressed in kidney and lung, while electrolytes resemble those of littermate controls. Challenge with a high K+ diet does not cause significant differences in blood K+, but provokes higher aldosterone in γmt/mt mice than controls. Quantitative magnetic resonance (QMR) measurement of body composition reveals similar baseline body water, lean tissue mass, and fat tissue mass in γmt/mt mice and controls. Surprisingly, euvolemia is sustained without significant changes in aldosterone or atrial natriuretic peptide. γmt/mt mice exhibit a more rapid decline in body water and lean tissue mass in response to a low Na+ diet than controls. Replacement of drinking water with 2% saline induces dramatic increases in body fat in both genotypes, and a selective transient increase in body water and lean tissue mass in γmt/mt mice. While ENaC in renal tubules and colon work to prevent extracellular fluid volume depletion, our observations suggest that ENaC in non-epithelial tissues may have a role in preventing extracellular fluid volume overload.