Red Blood Cell AE1/Band 3 Transports in Dominant Distal Renal Tubular Acidosis Patients

Jean-Philippe Bertocchio; Sandrine Genetet; Lydie Da Costa; Stephen B Walsh; Bertrand Knebelmann; Julie Galimand; Lucie Bessenay; Corinne Guitton; Renaud De Lafaille; Rosa Vargas-Poussou; Dominique Eladari; Isabelle Mouro-Chanteloup

doi:10.1016/j.ekir.2019.12.020

Red Blood Cell AE1/Band 3 Transports in Dominant Distal Renal Tubular Acidosis Patients

Kidney Int Rep. 2020 Jan 13;5(3):348-357. doi: 10.1016/j.ekir.2019.12.020. eCollection 2020 Mar.

Authors

Jean-Philippe Bertocchio^{1

2

3

4}, Sandrine Genetet^{5

6}, Lydie Da Costa^{5

7

8}, Stephen B Walsh⁹, Bertrand Knebelmann¹⁰, Julie Galimand⁸, Lucie Bessenay¹¹, Corinne Guitton¹², Renaud De Lafaille¹³, Rosa Vargas-Poussou^{3

14

15}, Dominique Eladari^{16

17}, Isabelle Mouro-Chanteloup^{5

6}

Affiliations

¹ Renal and Metabolic Diseases Unit, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital, Paris, France.
² Faculty of Medicine, Paris Descartes University, Paris, France.
³ Reference Center for Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France.
⁴ Genito-urinary Medical Oncology and Research Department, MD Anderson Cancer Center, Houston, Texas, USA.
⁵ UMR_S1134, Integrated Red Globule Biology (IRGB), Inserm, University of Paris, Paris, France.
⁶ Team 1, Physiology of Normal and Pathologic Red Blood Cell, Institut National de la Transfusion Sanguine (INTS), Paris, France.
⁷ UMR_S1134, Inserm, Paris, France.
⁸ Service d'Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris, France.
⁹ Department of Renal Medicine, University College of London, London, UK.
¹⁰ Nephrology Department, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France.
¹¹ Pediatrics Department, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France.
¹² Pediatrics Department, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France.
¹³ Nephrology Department, University Hospital of Bordeaux, Bordeaux, Aquitaine, France.
¹⁴ Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche UMRS1138, Cordeliers Research Center, Paris, France.
¹⁵ Genetics Department, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital, Paris, France.
¹⁶ Renal and Metabolic Diseases Department, CHU de la Réunion, Felix Guyon Hospital, Saint Denis, France.
¹⁷ INSERM, UMRS 1283-European Genomic Institute for Diabetes, Lille, France.

Abstract

Introduction: Anion exchanger 1 (AE1) (SLC4A1 gene product) is a membrane protein expressed in both kidney and red blood cells (RBCs): it exchanges extracellular bicarbonate (HCO₃ ^-) for intracellular chloride (Cl^-) and participates in acid-base homeostasis. AE1 mutations in kidney α-intercalated cells can lead to distal renal tubular acidosis (dRTA). In RBC, AE1 (known as band 3) is also implicated in membrane stability: deletions can cause South Asian ovalocytosis (SAO).

Methods: We retrospectively collected clinical and biological data from patients harboring dRTA due to a SLC4A1 mutation and analyzed HCO₃ ^- and Cl^- transports (by stopped-flow spectrophotometry) and expression (by flow cytometry, fluorescence activated cell sorting, and Coomassie blue staining) in RBCs, as well as RBC membrane stability (ektacytometry).

Results: Fifteen patients were included. All experience nephrolithiasis and/or nephrocalcinosis, 2 had SAO and dRTA (dRTA SAO+), 13 dominant dRTA (dRTA SAO-). The latter did not exert specific RBC membrane anomalies. Both HCO₃ ^- and Cl^- transports were lower in patients with dRTA SAO+ than in those with dRTA SAO- or controls. Using 3 different extracellular probes, we report a decreased expression (by 52%, P < 0.05) in dRTA SAO+ patients by fluorescence activated cell sorting, whereas total amount of protein was not affected.

Conclusion: Band 3 transport function and expression in RBCs from dRTA SAO- patients is normal. However, in SAO RBCs, impaired conformation of AE1/band 3 corresponds to an impaired function. Thus, the driver of acid-base defect during dominant dRTA is probably an impaired membrane expression.

Keywords: acidosis, renal tubular; anion exchange protein 1; erythrocyte; hematologic diseases; nephrocalcinosis; nephrolithiasis.