ESPN 54th Annual Meeting

ESPN 2022


 
A variant of ASIC2 mediates sodium retention in nephrotic syndrome
MARC FILA 1 ALI SASSI 2 GAELLE BRIDEAU 2 LYDIE CHEVAL 2 LUCIANA MORLA 2 MICHEL PEUCHMAUR 1 GEORGES DESCHENES 3 GILLES CRAMBERT 2 ALAIN DOUVCET 1

1- PEDIATRIC NEPHROLOGY DEPARTMENT CHU ARNAUD DE VILLENEUVE -MONTPELLIER UNIVERSITY
2- CORDELIERS RESEARCH CENTER, SORBONNE UNIVERSITY INSERM LABORATORY OF RENAL METABOLISM AND PHYSIOLOGY-CNRS ERL 8228 - PARIS PARIS
3- PEDIATRIC NEPHROLOGY DEPARTMENT - CHU ROBERT DEBRé APHP PARIS
 
Introduction:

 Idiopathic nephrotic syndrome (INS) is characterized by proteinuria and renal Na retention leading to oedema. This Na retention is usually attributed to epithelial sodium channel (ENaC) activation following plasma aldosterone increase.  However, most nephrotic patients show normal aldosterone levels. 

Material and methods:

 We used a corticosteroid-clamped version of the PAN nephrotic rat model (CC-PAN) to attempt to identify the sodium entry pathway in these patients

Results:

 CC-PAN rat showed electrogenic and amiloride-sensitive sodium reabsorption in cortical collecting duct similar to that of PAN rats but no increase in expression or activation of ENaC. We isolated from CC-PAN rat kidney a cDNA encoding a variant of acid sensing ion channel 2b (ASIC2b) lacking most of its N-ter intracellular domain. Co-expression of truncated ASIC2b with ASIC2a in X. laevis oocytes induced acid-stimulated sodium currents which were not transient but lasted as long as the stimulus remained. Interestingly, in ASIC2b-null rats generated by CRISPR-Cas9 technology, the injection of PAN did not induce sodium retention. Expression of ASIC2a and of truncated ASIC2b was increased in the ASDN of CC-PAN rats. ASIC2a and truncated-ASIC2b thus constitute channels supporting epithelial sodium reabsorption. Expression of truncated ASIC2b was abolished in albumin deficient rats and in rats treated with ERK kinase inhibitor. ASIC2 mRNA was also detected in kidney biopsies from patients with idiopathic nephrotic syndrome but in any of the patients with other renal diseases. In ASIC2-positive nephrotic patients, ASIC2 was expressed in ASDN.

Conclusions:

 

We have, therefore, identified a novel variant of ASIC2b responsible for the renal Na retention in the pathological context of INS.