A variant of ASIC2 mediates sodium retention in nephrotic syndrome
Marc Fila, Ali Sassi, Gaëlle Brideau, Lydie Cheval, Luciana Morla, Pascal Houillier, Christine Walter, Michel Gennaoui, Laure Collignon, Mathilde Keck, Gabrielle Planelles, Naziha Bakouh, Michel Peuchmaur, Georges Deschênes, Ignacio Anegon, Séverine Remy, Bruno Vogt, Gilles Crambert, Alain Doucet
Marc Fila, Ali Sassi, Gaëlle Brideau, Lydie Cheval, Luciana Morla, Pascal Houillier, Christine Walter, Michel Gennaoui, Laure Collignon, Mathilde Keck, Gabrielle Planelles, Naziha Bakouh, Michel Peuchmaur, Georges Deschênes, Ignacio Anegon, Séverine Remy, Bruno Vogt, Gilles Crambert, Alain Doucet
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Research Article Nephrology

A variant of ASIC2 mediates sodium retention in nephrotic syndrome

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.

Authors

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

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Figure 9

ERK pathway is triggered by luminal albumin.

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ERK pathway is triggered by luminal albumin. (A) Immunolabeling of kidne...
(A) Immunolabeling of kidney cortical sections from CC-WT rats and CC-NARs under control and PAN nephrotic condition with anti-phospho-ERK (red) and AQP2 (in green). AQP2 was used as a marker of CCDs. Left side shows representative images of phosphorylation of ERK in nephrotic WT rats but not in NARs. Right side shows the quantification of phospho-ERK labeling in CCDs. Values were normalized to the labeling measured in each experiment in the same CC control WT rat. Data are shown as mean ± SEM (n = 4–8). (B) Same immunolabeling as in A in CC-PAN WT rats treated or not with the ERK kinase inhibitor U0126. Data are shown as mean ± SEM (n = 4–6). Comparison between groups was performed by variance analysis (1-way ANOVA) followed by post hoc multiple comparison Tukey’s test (A) or by 2-tailed unpaired t test (B). P < 0.05. CCDs, cortical-collecting ducts; CC, corticosteroid-clamped.