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A Mouse Model of Pseudohypoaldosteronism Type II Reveals a Novel Mechanism of Tenal Tubular Acidosis Irma Karen Lopez-Cayuqueo

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A Mouse Model of Pseudohypoaldosteronism Type II Reveals a Novel Mechanism of Tenal Tubular Acidosis Irma Karen Lopez-Cayuqueo A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of tenal tubular acidosis Irma Karen Lopez-Cayuqueo To cite this version: Irma Karen Lopez-Cayuqueo. A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of tenal tubular acidosis. Tissues and Organs [q-bio.TO]. Sorbonne Université, 2018. English. NNT : 2018SORUS465. tel-02926159 HAL Id: tel-02926159 https://tel.archives-ouvertes.fr/tel-02926159 Submitted on 31 Aug 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Sorbonne Université Ecole doctorale: Physiologie, Physiopathologie et Thérapeutique. ED394 THÈSE DE DOCTORAT Présentée par: Melle Irma Karen LÓPEZ-CAYUQUEO A Mouse Model of Pseudohypoaldosteronism type II Reveals a Novel Mechanism of Renal Tubular Acidosis Dirigée par: Dr. Régine Chambrey Soutenue le 27-04-2018 Devant un jury composé de: Prof. Pierre Ronco Président du Jury Prof. Renaud Beauwens Rapporteur Dr. Henrik Dimke Rapporteur Dr. Maria Christina Zennaro Examinateur Dr. Régine Chambrey Examinateur Prof. Jacques Teulon Directeur de thèse LANGUE DE REDACTION Avec la permission de l’école doctorale de l’UPMC (ED394), la thèse a été rédigée en anglais, ma langue de recherche et de publication usuelle. 2 PREFACE The experiments relative to this work were mostly done during the first 2 years of my PhD under the supervision of Dr. Régine Chambrey at the Paris Cardiovascular Research Center (PARCC). Part of the experiments shown in this work were performed in collaboration with, or exclusively by professor Pascal Houillier (Figure 17) and Dr. Régine Chambrey (Figure 10). Contribution of all the authors of the paper “A Mouse Model of Pseudohypoaldosteronism type II Reveals a Novel Mechanism of Renal Tubular Acidosis”, submitted to Kidney International, is acknowledged. During the last year of my PhD, to complete my doctoral formation I performed a long-term internship in the laboratory of Professor Thomas Jentsch at the Leibniz- Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund (FMP) / Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC). Berlin, Germany. The research performed during this time will not be presented in this thesis. 3 TABLE OF CONTENTS LIST OF FIGURES ..................................................................................................................... 6 LIST OF TABLES ....................................................................................................................... 7 LIST OF ABBREVIATIONS ......................................................................................................... 8 ABSTRACT .............................................................................................................................. 10 1. INTRODUCTION .................................................................................................................. 11 1.1 Overview of kidney structure and function ....................................................................... 11 1.2 Renal physiopathology .................................................................................................... 13 1.2.1 Sodium handling along the nephron and associated pathologies .................................. 14 1.2.2 Potassium handling and its physiological consequences .............................................. 23 1.3 Acid-base homeostasis ................................................................................................... 24 1.4 Pseudohypoaldosteronism type II .................................................................................... 25 1.4.1 Physiopathology of PHAII ............................................................................................. 26 1.4.1.1 Regulation of NCC ..................................................................................................... 27 1.4.1.2 Impact of WNK pathway in NCC regulation and in the pathogenesis of PHAII ........... 27 1.4.1.3 Influence of the electroneutral NaCl reabsorption in the pathogenesis of PHAII ........ 33 1.4.1.3.1 Additional information about Pendrin and NDCBE .................................................. 33 2. AIM OF THE WORK ............................................................................................................. 35 3. MATERIALS AND METHODS .............................................................................................. 36 3.1 Animal generation and physiological studies ................................................................... 36 3.2 Blood gas and urinary analysis ........................................................................................ 36 3.3 Potassium diet and ammonium load ................................................................................ 37 3.4 Intracellular pH measurements on isolated microperfused tubules .................................. 37 3.5 Measure of the fractional volume ..................................................................................... 38 3.6 Measurements of blood pressure by radiotelemetry ........................................................ 39 3.7 Immunoblotting ................................................................................................................ 39 3.8 Real-time quantitative RT-PCR ....................................................................................... 40 3.9 Intercalated cell type quantification .................................................................................. 41 3.10 Antibody sources ........................................................................................................... 41 3.11 In vitro microperfusion of mouse CCDs and transepithelial ion flux measurement ......... 42 3.12 Statistics and data analysis ........................................................................................... 43 3.13 Study approval .............................................................................................................. 43 4. RESULTS ............................................................................................................................. 44 4.1 TgWnk4PHAII mice exhibit hyperkalemic metabolic acidosis .............................................. 44 4.2 Electroneutral thiazide-sensitive NaCl transport is activated in the collecting duct of TgWnk4PHAII mice .................................................................................................................. 46 4.3 ENaC-dependent K+ secretion is blocked in TgWnk4PHAII mice despite unchanged renal ENaC activity ................................................................................................................ 48 4.4 Normalization of plasma K+ concentration does not correct metabolic acidosis in TgWnk4PHAII mice .................................................................................................................. 51 4.5 Renal acidosis in TgWnk4PHAII mice is not caused by impaired proton secretion by the distal nephron .................................................................................................................. 52 4.6 Renal acidosis in TgWnk4PHAII mice is a consequence of an increased of the pendrin activity ................................................................................................................................... 56 4 4.7 Hyperchloremic metabolic acidosis and hyperkalemia in TgWnk4PHAII mice are corrected by pendrin genetic ablation. ................................................................................... 60 5. DISCUSSION ....................................................................................................................... 65 5.1 The NCC upregulation is not sufficient to explain entire the phenotypic features of PHAII ..................................................................................................................................... 65 5.2 Pendrin overactivity is contributing to the pathogenesis of PHAII .................................... 67 5.3 Impact of pendrin deletion on plasma K+ concentration of TgWnk4PHAII mice ................... 68 5.4 Pendrin hyperactivity as a novel mechanism for renal acidosis ....................................... 70 5.5 The missing link between pendrin regulation and WNK4 ................................................. 71 5.6 Conclusion ...................................................................................................................... 72 6. PUBLICATIONS.................................................................................................................... 74 7. ACKNOWLEDGMENTS ........................................................................................................ 77 8. REFERENCES ..................................................................................................................... 78 5 LIST OF FIGURES Figure 1. Structure of the nephron……………………………………..……………………….12 Figure 2. Sodium handling along the nephron..……………………………………………….14
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