The role of LPA in kidney pathologies Koryun Mirzoyan To cite this version: Koryun Mirzoyan. The role of LPA in kidney pathologies. Human health and pathology. Université Paul Sabatier - Toulouse III, 2017. English. NNT : 2017TOU30073. tel-01825826 HAL Id: tel-01825826 https://tel.archives-ouvertes.fr/tel-01825826 Submitted on 28 Jun 2018 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. 5)µ4& &OWVFEFMPCUFOUJPOEV %0$503"5%&-6/*7&34*5²%&506-064& %ÏMJWSÏQBS Université Toulouse 3 Paul Sabatier (UT3 Paul Sabatier) 1SÏTFOUÏFFUTPVUFOVFQBS Koryun MIRZOYAN le mercredi 20 septembre 2017 5JUSF The role of LPA in kidney pathologies ²DPMFEPDUPSBMF et discipline ou spécialité ED BSB : Physiopathologie 6OJUÏEFSFDIFSDIF INSERM U1048/I2MC - équipe 12 %JSFDUFVSUSJDF T EFʾÒTF Dr Jean-Sébastien Saulnier-Blache Jury: Pr Isabelle Castan-Laurell (Présidente du Jury) Dr Alberto Ortiz (Rapporteur) Dr Olivier Peyruchaud (Rapporteur) Dr Jean-Sébastien Saulnier-Blache (Directeur de thèse) Aknowledgements First of all I would like to thank all the members of the jury and reporters for generously accepting to evaluate my work and participating in my thesis defense. Thank you for your valuable advices and comments that highly improved the quality of the thesis. I would like to thank all organizers of the Erasmus Mundus MEDEA project and especially to Elodie Balonas and Oxana Kunduzova who made big efforts to realize this project and to give me the possibility for this wonderful journey full of with new knowledge, experience and adventures. Thanks to all members of team 12 who made the 3 years of lab-life filled with lot of work but also with fun and emotions: thanks to Julie, Colette, Bénédicte, Ben, Guylène, Eric, Marion, Dimitri, Stan for sharing the experience and knowledge, for the company, help and advices. Special thanks to Audrey, who discovered for me all the loveliness of biological experiments and taught me to work in the lab. Big thanks to Jean-Loup and Joost for accepting me in the team 12 and giving the opportunity to work within this nice team during 3 years. To PhD students after me, Valerie and Franck, thank you for your company, for belote, pétanque and beer evenings. Look always forward and work hard. The end of the PhD is not so far. To my mentor Jean-Sébastien: you are the kindest supervisor I have ever met. Thank you for everything, for your supervision, for the advices and the support you gave me. I hope we will meet in the future and continue to collaborate and work together. Big thanks to my family and all my friends in Armenia, in France and in other pieces all over the world. Without your support and encouragement it wouldn’t be possible to finish this work. 1 This thesis is dedicated to my parents Samvel Mirzoyan and Janna Sargsyan. 2 Index Abstract ..................................................................................................................................6 Résumé ..................................................................................................................................8 Figures and tables legends .................................................................................................... 10 Abbreviations ....................................................................................................................... 11 1. Introduction ...................................................................................................................... 13 1.1 The kidneys ................................................................................................................. 13 1.2 Kidney pathologies...................................................................................................... 14 1.2.1 Acute kidney injury .............................................................................................. 14 1.2.1.1 Definition and classification ........................................................................... 14 1.2.1.2 Epidemiology of AKI ..................................................................................... 17 1.2.1.3 Sepsis-induced AKI ........................................................................................ 17 1.2.1.3.1 Pathogenesis of sepsis-induced AKI ......................................................... 17 1.2.1.3.1.1 Hemodynamic changes ...................................................................... 17 1.2.1.3.1.2 Inflammation in sepsis-induced AKI .................................................. 19 1.2.1.3.1.3 Adaptive responses in tubular epithelial cells ..................................... 21 1.2.1.3.2 Treatment strategies ................................................................................. 21 1.2.2 Chronic kidney disease ......................................................................................... 22 1.2.2.1 Definition and classification ........................................................................... 22 1.2.2.2 Epidemiology of CKD .................................................................................... 23 1.2.2.3 CKD pathogenesis .......................................................................................... 24 1.2.2.3.1 Glomerulosclerosis .................................................................................. 24 1.2.2.3.2 Tubulo-interstitial fibrosis (TIF) .............................................................. 25 1.2.2.3.2.1 Inflammation ..................................................................................... 25 1.2.2.3.2.2 Appearance of ECM producing cells.................................................. 26 1.2.2.3.2.3 Pro-fibrotic cytokines ........................................................................ 27 1.2.2.3.2.4 Accumulation of ECM ....................................................................... 27 1.2.2.4 Progression of CKD ....................................................................................... 29 1.2.2.5 Therapeutic strategies ..................................................................................... 29 1.2.3 AKI and CKD are interconnected ......................................................................... 30 1.2.3.1 AKI is a risk factor for CKD .......................................................................... 30 1.2.3.1.1 The mechanisms of AKI progression to CKD ............................................ 30 1.2.4 Conclusions .......................................................................................................... 31 3 2. Lysophosphatidic acid ...................................................................................................... 32 2.1-Structure ..................................................................................................................... 32 2.2 Synthesis of LPA ........................................................................................................ 32 2.2.1 Intracellular synthesis ........................................................................................... 33 2.2.2 Extracellular synthesis .......................................................................................... 33 2.3 Degradation of LPA .................................................................................................... 34 2.4 Transport of LPA ........................................................................................................ 36 2.5 LPA in biologic fluids ................................................................................................. 36 2.5.1 LPA in blood ........................................................................................................ 36 2.5.2 LPA in other biological fluids. .............................................................................. 36 2.6 LPA receptors ............................................................................................................. 37 2.6.1 G-protein coupled membrane receptors ................................................................. 37 2.6.1.1. Classification and tissue distribution .............................................................. 37 2.6.1.2 Intracellular signaling pathways ..................................................................... 39 2.6.1.3 Relative specificity of LPA receptors towards different LPA species .............. 40 2.6.1.4 Genetic deletions and associated pathologies .................................................. 41 2.6.2 Intracellular receptors ........................................................................................... 43 2.6.3 Other potential receptors ....................................................................................... 44 2.6.4 LPA receptor antagonists ...................................................................................... 44 2.7 Physiological and pathophysiological effects of LPA .................................................. 45 2.7.1 Cancer .................................................................................................................