Salt restriction induces pseudohypoaldosteronism type 1 in mice expressing low levels of the β-subunit of the amiloride-sensitive epithelial sodium channel

Abstract

The amiloride-sensitive epithelial sodium channel (ENaC) is a heteromultimer of three homologous subunits (␣-, ␤-, and ␥-subunits). To study the role of the ␤-subunit in vivo, we analyzed mice in which the ␤ENaC gene locus was disrupted. These mice showed low levels of ␤ENaC mRNA expression in kidney (Ϸ1%), lung (Ϸ1%), and colon (Ϸ4%). In homozygous mutant ␤ENaC mice, no ␤ENaC protein could be detected with immunof luorescent staining. At birth, there was a small delay in lung-liquid clearance that paralleled diminished amiloride-sensitive Na ؉ absorption in tracheal explants. With normal salt intake, these mice showed a normal growth rate. However, in vivo, adult ␤ENaC m͞m mice exhibited a significantly reduced ENaC activity in colon and elevated plasma aldosterone levels, suggesting hypovolemia and pseudohypoaldosteronism type 1. This phenotype was clinically silent, as ␤ENaC m͞m mice showed no weight loss, normal plasma Na ؉ and K ؉ concentrations, normal blood pressure, and a compensated metabolic acidosis. On low-salt diets, ␤ENaC-mutant mice developed clinical symptoms of an acute pseudohypoaldosteronism type 1 (weight loss, hyperkalemia, and decreased blood pressure), indicating that ␤ENaC is required for Na ؉ conservation during salt deprivation.

Invited Review: Clearance of lung liquid during the perinatal period

“…Knockout mice for all three ENaC subunits have been reported (11,36,46), and additional ENaC mutants have been studied (37,57). The most striking finding was that mutant newborns lacking the ␣-ENaC gene were unable to clear lung liquid from the alveolar spaces after birth ( Fig.…”

Af17 Deficiency Increases Sodium Excretion and Decreases Blood Pressure

“…Indeed, such coupling was not observed in Sgk1 Ϫ/Ϫ , 17,37 AS Ϫ/Ϫ , 13 ␣ENaC( Ϫ/Ϫ )Tg, 38 and ␤ENaC m/m mice. 39 Although Sgk1 ϩ/ϩ and Sgk1 Ϫ/Ϫ mice did not display a significant difference in urinary Na ϩ excretion on a normal Na ϩ diet, their plasma [K ϩ ] was significantly different. 40 Morever, the significantly increased Na ϩ excretion was not coupled with markedly decreased K ϩ excretion and was instead paralleled by increased K ϩ excretion during the early phases of Na ϩ restriction in Sgk1 Ϫ/Ϫ versus Sgk1 ϩ/ϩ mice.…”

“…38 Similarly, significantly elevated urinary [Na ϩ ]/[creatinine] and plasma [K ϩ ] in ␤ENaC m/m mice on a low Na ϩ diet were not accompanied with the expected changes in the urinary excretion of Na ϩ , K ϩ , and plasma [Na ϩ ]. 39 The most striking feature differing Af17 Ϫ/Ϫ from others identifiedthusfarliesinitsresponsetoaldo.Therenalphysiologyand BP phenotype in Af17 Ϫ/Ϫ mice is [aldo] dependent. Nevethereless, dramaticallyelevatedplasma[aldo]canrescueneithertherenalphysiology and BP phenotype of Sgk1 Ϫ/Ϫ nor the salt wasting of MR Ϫ/Ϫ mice.…”

Transgenic mice and their impact on kidney research

“…Over the past years, we have generated an allelic series of mutations at the ENaC (Scnn1) gene loci showing that any modified expression the ENaC subunits may cause a kidney disease [4,36,39,74,76,111]. Constitutive gene inactivation of all three subunits revealed that the absolute ENaC expression is essential for survival [4,35,59].…”

“…Various mouse lines have been generated in which the ENaC activity ranges from hypoactive channels (5-15% of total ENaC activity) to hyperactive channels (>150% of total ENaC activity; for review, see [37]. Reduced ENaC activity in mice bearing ENaC mutations led to clinical symptoms similar to PHA-1 (pseudohypoaldosteronism type 1) ranging from mild (e.g., mutation in the ßENaC gene locus [74]) to severe phenotype (e.g., γENaC knockout mice [4]). We further introduced one of the classical Liddle mutations (R566STOP) into the mouse ßENaC (Scnn1b) gene locus, thereby generating mice, which reproduce to a large extent the clinical symptoms of Liddle patients [76].…”