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 ENaCs subunits results in early post-natal mortality. We present initial characterization of a mouse with dramatically suppressed expression of the {gamma} subunit. We use this hypomorphic ({gamma}mt) allele to explore the importance of ENaCs {gamma} subunit in homeostasis of electrolytes and body fluid volume. At baseline, {gamma} subunit expression in {gamma}mt/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 {gamma}mt/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 {gamma}mt/mt mice and controls. Surprisingly, euvolemia is sustained without significant changes in aldosterone or atrial natriuretic peptide. {gamma}mt/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 {gamma}mt/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.