Regulation of sodium transport by ENaC in the kidney

Abstract

Purpose of review: The amiloride-sensitive epithelial sodium channel (ENaC) plays a major role in the regulation of sodium transport in the collecting duct and hence sodium balance. This review describes recent findings in the regulation of ENaC function by serine proteases in particular and other regulatory aspects.

Recent findings: Regulation of ENaC occurs at many levels (biophysical, transcriptional, post-translational modifications, assembly, membrane insertion, retrieval, recycling, degradation, etc.). Recent studies have recognized and delineated proteolytic cleavage, particularly of the alpha and gamma subunits, as major mechanisms of activation. Release of peptide fragments from these two subunits appears to be an important aspect of activation. These proteolytic mechanisms of ENaC activation have also been demonstrated in vivo and strongly suggested in clinical circumstances, particularly the nephrotic syndrome. In the nephrotic syndrome, filtered plasminogen may be cleaved by tubular urokinase to yield plasmin which can activate ENaC. In addition to these mechanisms, regulation by ubiquitination and deubiquitination represents a pivotal process. Several important deubiquitinating enzymes have been identified as important in ENaC retention in, or recycling to, the apical membrane. New aspects of the genomic control of ENaC transcription have also been found including histone methylation.

Summary: The mechanisms of regulation of ENaC are increasingly understood to be a complex interplay of many different levels and systems. Proteolytic cleavage of alpha and gamma subunits plays a major role in ENaC activation. This may be particularly clinically relevant in nephrotic syndrome in which plasmin may activate ENaC activity.

Figure 1

Model of proteolytic cleavage sites in α and γ ENaC subunits by furin, prostasin, neutrophil and pancreatic elastase, plasmin, CAP2 and trypsin. Adapted from refs. and .. The dashed line is shown to illustrate possible inhibitory fragments cleaved from these two subunits for ENaC activation.

Figure 2

Model of the regulation of Na transport in collecting duct principal cells. Ubiquitin ligase Nedd4-2 and deubiquitinase Usp2-45 reciprocally regulate ubiquitination and recycling of ENaC. Aldosterone regulates gene expression of ENaC subunits via Sgk1-induced phosphorylation of Af9 and PLZF-dependent repression. Sgk1 regulates ENaC function via inhibition of Nedd4-2 dependent ubiquitination. Aldosterone and TGF-β1 reciprocally regulate ENaC function via antagonistic influence on PN-1 expression. MR, mineralocorticoid receptor; PN-1, protease nexin 1; U, ubiquitin; Sgk1, Serum- and glucocorticoid-inducible kinase 1; PLZF, promyelocytic leukaemia zinc finger protein; Dot1a, disruptor of telomeric silencing alternative splice variant a; Af9, ALL1-fused gene from chromosome 9.