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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 7

Expression of ASIC2 in nephrotic patients.

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Expression of ASIC2 in nephrotic patients.
(A) RT-qPCR analysis of ASIC2...
(A) RT-qPCR analysis of ASIC2 mRNA in kidney biopsies from patients with NGN (n = 11) or INS (n = 8). Given the heterogeneity of biopsies in term of cell composition, data were standardized using distal nephron markers, as previously described (38). Data are in arbitrary units. (B) Immunolabeling of kidney serial sections with anti-AQP2 (red) and anti-ASIC2 antibody (b and d, green) from a patient with INS (upper panels) or a nonnephrotic patient (lower panels). Scale bar: 100 μm. Comparison between groups was performed by 2-tailed unpaired t test. P < 0.05. ASIC2, acid-sensing ion channel; NGN, nonglomerular nephropathies; INS, idiopathic nephrotic syndrome.

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