Respiratory distress and perinatal lethality in Nedd4-2-deficient mice

Abstract

The epithelial sodium channel (ENaC) is essential for sodium homoeostasis in many epithelia. ENaC activity is required for lung fluid clearance in newborn animals and for maintenance of blood volume and blood pressure in adults. In vitro studies show that the ubiquitin ligase Nedd4-2 ubiquitinates ENaC to regulate its cell surface expression. Here we show that knockout of Nedd4-2 in mice leads to increased ENaC expression and activity in embryonic lung. This increased ENaC activity is the likely reason for premature fetal lung fluid clearance in Nedd4-2−/− animals, resulting in a failure to inflate lungs and perinatal lethality. A small percentage of Nedd4-2−/− animals survive up to 22 days, and these animals also show increased ENaC expression and develop lethal sterile inflammation of the lung. Thus, we provide critical in vivo evidence that Nedd4-2 is essential for correct regulation of ENaC expression, fetal and postnatal lung function and animal survival.

Rac1 acts in conjunction with Nedd4 and Dishevelled-1 to promote maturation of cell-cell contacts

“…Mice deficient for Nedd4-2 show a different phenotype. Here, loss of Nedd4-2 increases the expression of the sodium channel ENaC, resulting in impaired lung function and perinatal death (Boase et al, 2011). It might be that the epithelial phenotype of Nedd4 deficiency that we report here becomes more apparent after birth or that Nedd4 and Nedd4-2 are functionally redundant in the regulation of epithelial junctions in vivo.…”

Ubiquitylation and the pathogenesis of hypertension

“…Although both the nephron-specific (8) and global Nedd4-2-knockout (10) mice are viable and appear healthy, a third model of Nedd4-2-knockout exhibited perinatal mortality due to pulmonary dysfunction (11). Both of the viable models inactivate Nedd4-2 by deleting exons 6-8, while the mice with lethality had exons 15 and 16 deleted.…”

Endocytic regulation of alkali metal transport proteins in mammals, yeast and plants

“…These mutations lead to the overaccumulation of the ENaC channel, which causes increased Na + reabsorption by the kidneys and leads to hypertension (Shimkets, et al 1994). Further studies and the generation of nedd4-2 -/-mouse models have established that it is Nedd4-2, and not Nedd4, which plays an important physiological role in down-regulating ENaC by catalyzing its ubiquitylation, which leads to its degradation in the lysosome (Figure 1) (Boase, et al 2011. The first mouse model generated by Shi and colleagues suggested that Nedd4-2 function was not necessary for proper development.…”

“…Nedd4 was subsequently found to be widely expressed, whereas Nedd4-2 is expressed mainly in lung, heart, kidney, brain, and liver (Kumar, et al 1997, Yang andKumar 2010). Despite their sequence similarity, Nedd4 and Nedd4-2 have different physiological functions, as shown by a systematic analysis of their substrates and the different phenotypes presented by mouse knock-out models (Boase, et al 2011, Persaud, et al 2009. The function of Nedd4 is related to the control of cell growth, as nedd4 -/-knock-out mice display growth retardation (with a 60% reduction in body weight compared to wild type littermates) and associated perinatal lethality ).…”

“…These phenotypes were attributable to increased ENaC activity based on biochemical analysis of ENaC protein levels and phenotypic improvement upon treatment with the ENaC-specific inhibitor, amiloride. More recently, a second knock-out mouse was constructed in an inbred genetic background (Boase, et al 2011). In this case, the phenotypes were more severe, leading to perinatal death of the pups caused by failure to inflate the lungs due to increased ENaC activity in this tissue.…”