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A variant of ASIC2 mediates sodium retention in nephrotic syndrome
Marc Fila, … , Gilles Crambert, Alain Doucet
Marc Fila, … , Gilles Crambert, Alain Doucet
Published June 24, 2021
Citation Information: JCI Insight. 2021;6(15):e148588. https://doi.org/10.1172/jci.insight.148588.
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Research Article Nephrology

A variant of ASIC2 mediates sodium retention in nephrotic syndrome

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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 2

Role of ASIC2b in sodium retention in CC-PAN rats.

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Role of ASIC2b in sodium retention in CC-PAN rats.
(A) RT-qPCR analysis ...
(A) RT-qPCR analysis of ENaC/degenerin mRNA in CCDs from CC-PAN rats. Data are expressed as percent of values in CC control rats. Data are shown as mean ± SEM (each value represents a rat). (B) Proteinura in WT (n = 7) and ASIC2b–/– CC-PAN (n = 13) rats. Proteinuria is expressed as a function of creatinine excretion. Data are shown as mean ± SEM (each value represents a rat). (C) JNa+ in CCDs from WT and ASIC2b–/– rats under basal (C) or nephrotic (PAN) conditions. Data are shown as mean ± SEM (each value represents a rat, n = 6–7). (D) Urinary sodium balance in WT and ASIC2b–/– rats under basal (C) or nephrotic (PAN) conditions. Data are shown as mean ± SEM (each value represents a rat, n = 7–12). (E) Volume of ascites, as a function of body weight, in WT (n = 7) and ASIC2b–/– CC-PAN (n = 11) rats. Data are shown as mean ± SEM. 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–E). P < 0.05. ASIC2b, acid-sensing ion channel 2b; CCDs, cortical-collecting ducts; CC, corticosteroid-clamped; ENaC, epithelial sodium channel.

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