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 11

Reversal of sodium retention.

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Reversal of sodium retention. (A) Proteinuria, sodium balance and volume...
(A) Proteinuria, sodium balance and volume of ascites in CC rats under control condition (C) or 6 or 12 days after PAN administration. Data are shown as mean ± SEM (n = 7–11). (B) Immunolabeling of kidney cortex section from CC rats under control condition (C) or 6 or 12 days after PAN administration with an anti-albumin antibody (green) and AE1 antibody (red), a specific marker of CCD intercalated cells. *, CCD; $, proximal tubule. Scale bar: 25 μm. (C) Immunolabeling of kidney cortex section from CC rats under control condition (C) or 6 or 12 days after PAN administration with an anti-phospho-ERK antibody (red) and an anti-AQP2 antibody (green), a specific marker of CCD principal cells. Left, representative images; right, quantification as in Figure 8A. Data are shown as mean ± SEM (n = 4). (D) Expression of Asic2b mRNA in CCDs from CC rats under control condition (C) or 6 or 12 days after PAN administration. Data are shown as mean ± SEM (n = 4–7). Comparison between groups was performed by variance analysis (1-way ANOVA) followed by post hoc multiple comparison Tukey’s test. P < 0.05. CC, corticosteroid-clamped; CCDs, cortical-collecting ducts.