A variant of ASIC2 mediates sodium retention in nephrotic syndrome.

Marc Fila,Luciana Morla,Ignacio Anegon,Gaelle Brideau,Mathilde Keck,Michel Peuchmaur,Séverine Remy,Christine Walter,Ali Sassi,Naziha Bakouh,Gabrielle Planelles,Bruno Vogt,Michel Gennaoui,Laure Collignon,Alain Doucet,Pascal Houillier,Georges Deschenes,Lydie Cheval,Gilles Crambert

doi:10.1172/jci.insight.148588

Abstract

Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal sodium retention leading to edema. This sodium retention is usually attributed to epithelial sodium channel (ENaC) activation after plasma aldosterone increase. However, most nephrotic patients show normal aldosterone levels. Using a corticosteroid-clamped (CC) rat model of INS (CC-PAN), we showed that the observed electrogenic and amiloride-sensitive Na retention could not be attributed to ENaC. We then identified a truncated variant of acid-sensing ion channel 2b (ASIC2b) that induced sustained acid-stimulated sodium currents when coexpressed with ASIC2a. Interestingly, CC-PAN nephrotic ASIC2b-null rats did not develop sodium retention. We finally showed that the expression of the truncated ASIC2b in the kidney was dependent on the presence of albumin in the tubule lumen and activation of ERK in renal cells. Finally, the presence of ASIC2 mRNA was also detected in kidney biopsies from patients with INS but not in any of the patients with other renal diseases. We have therefore identified a variant of ASIC2b responsible for the renal Na retention in the pathological context of INS.

Highlights

Nephrotic syndrome is defined by the association of massive proteinuria with hypoalbuminemia brought about by dysfunctions of the glomerular filtration barrier
Sodium retention originated from collecting ducts of CC-puromycin aminonucleoside–induced rat model of nephrotic syndrome (PAN rat) but was independent of the ENaC
JNa+ in collecting ducts (CCDs) from LNa rats was markedly reduced after luminal addition of 300 μM ZnCl2 whereas it was slightly increased in CC-PAN rats (Figure 1C)

Summary

Introduction

Nephrotic syndrome is defined by the association of massive proteinuria with hypoalbuminemia brought about by dysfunctions of the glomerular filtration barrier. Idiopathic nephrotic syndrome (INS) is associated with sodium retention, which participates in the formation of ascites and edema [1]. To PAN rats most nephrotic patients display normal volemia and plasma aldosterone levels [7]. This raises the possibility that the site and mechanism of sodium retention in most nephrotic patients might be different from those described in PAN rats. As a matter of fact, when their plasma level of corticosteroids is clamped to basal level, PAN rats still develop nephrotic syndrome and amiloride-sensitive edema and ascites, but the mechanism of sodium retention is different because they display no membrane expression and activity of ENaC in the ASDN [6, 8]. The secondary aim was to evaluate whether this alternate sodium reabsorption pathway is present in nephrotic patients

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