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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 1

Sodium flux (JNa+) measured in microperfused CCDs in vitro.

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Sodium flux (JNa+) measured in microperfused CCDs in vitro.
(A) JNa+ in ...
(A) JNa+ in CCDs from PAN nephrotic and CC-PAN nephrotic rats (PAN n = 8 and CC-PAN n = 6). Data are shown as mean ± SEM (each value represents a rat). (B) JNa+ was measured in CCDs from CC-PAN nephrotic rats before (B) and after (A) luminal addition of 10 μM amiloride. Each value represents a tubule (n = 3). (C) JNa+ in CCDs from CC-PAN rats and rats fed a LNa diet for 14 days before and after luminal addition of 300 μM ZnCl2. Each value represents a tubule (n = 6 and n = 4 in CC-PAN and LNa condition, respectively). (D) JNa+ in CCDs from CC-PAN and LNa rats was measured before and after acidification of the luminal fluid at pH 6.0. Each value represents a tubule (n = 4 and n = 5 in CC-PAN and LNa condition, respectively). Comparison between groups was performed by either 2-tailed unpaired t test (A) or paired t test (B–D). P < 0.05. CCDs, cortical-collecting ducts; CC, corticosteroid-clamped; LNa, sodium-depleted.

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