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Allard Julien.Pdf TTHHÈÈSSEE En vue de l'obtention du DOCTORAT DE L’UNIVERSITÉ DE TOULOUSE Délivré par l'Université Toulouse III - Paul Sabatier Discipline ou spécialité : Physiopathologie expérimentale Présentée et soutenue par Julien ALLARD Le 15 septembre 2010 Titre : Bradykinine et oestradiol : médiateurs endogènes d'intérêt pour la néphroprotection au cours du diabète expérimental JURY Docteur Jean-Pierre GIROLAMI - Président Professeur Jean-Claude DUSSAULE - Rapporteur Docteur François ALHENC-GELAS - Rapporteur Professeur Marie ESSIG - Examinatrice Professeur Jean-François ARNAL - Examinateur Professeur Ivan TACK - Directeur de thèse Ecole doctorale : Biologie, Santé et Biotechnologies Unité de recherche : INSERM U858 - Equipe 5 Directeur(s) de Thèse : Pr. Ivan TACK Rapporteurs : Pr. J-C. DUSSAULE et Dr. F. ALHENC-GELAS UNIVERSITE TOULOUSE III – PAUL SABATIER Ecole doctorale Biologie, Santé et Biotechnologies THESE Pour l’obtention du grade de DOCTEUR DE L’UNIVERSITE TOULOUSE III Physiopathologie expérimentale Présentée et soutenue par Julien Allard le 15 septembre 2010 Bradykinine et œstradiol : médiateurs endogènes d’intérêt pour la néphroprotection au cours du diabète expérimental JURY Professeur Jean-Claude Dussaule Rapporteur Docteur François Alhenc-Gelas Rapporteur Docteur Jean-Pierre Girolami Examinateur Professeur Marie Essig Examinatrice Prosesseur Jean-François Arnal Examinateur Professeur Ivan Tack Directeur de thèse INSERM U858 - Equipe 5 – Néphroprotection : Des mécanismes Physiopathologiques aux Cibles Thérapeutiques Institut de Médecine Moléculaire de Rangueil, CHU Rangueil, Toulouse Sommaire SOMMAIRE SOMMAIRE.................................................................................................................................................. 2 PRINCIPALES ABREVIATIONS UTILISEES ........................................................................................ 4 LA NÉPHROPATHIE DIABÉTIQUE............................................................................................................ 7 I. PHYSIOPATHOLOGIE DE LA NEPHROPATHIE DIABETIQUE.............................................................. 8 I.1. L’hyperglycémie chronique et les AGEs .............................................................................................. 10 I.2. Le stress oxydant : pivot de la réaction cellulaire à l’hyperglycémie.................................................... 11 I.3. Le NO ................................................................................................................................................... 12 I.4. Le Système rénine-angiotensine (SRA) ................................................................................................ 13 I.5. Les facteurs de croissance..................................................................................................................... 14 I.5.1. L’IGF-1 ........................................................................................................................................... 14 I.5.2. Le TGF beta..................................................................................................................................... 15 I.5.3. Le PDGF, le FGF et le CTGF.......................................................................................................... 15 I.5.4. Le VEGF ......................................................................................................................................... 16 I.6. L’inflammation ..................................................................................................................................... 17 I.7. L’hypoxie.............................................................................................................................................. 17 II. THERAPEUTIQUES ACTUELLES ET PERSPECTIVES ........................................................................ 18 II.1. A la recheche d’une stratégie ................................................................................................................ 18 II.2. La fibrose rénale est elle réversible ?.................................................................................................... 19 II.3. Les approches pharmacologiques.......................................................................................................... 20 II.3.1. Le blocage du système rénine-angiotensine..................................................................................... 20 II.3.2. Le blocage de la PKC beta............................................................................................................... 21 II.3.3. Les thiazolidinediones ..................................................................................................................... 21 II.3.4. Le HGF............................................................................................................................................ 21 II.3.5. Les inhibiteurs des histones desacethylases..................................................................................... 22 II.4. Autres cibles thérapeutiques potentielles .............................................................................................. 22 II.4.1. Le maintien de l’intégrité podocytaire via l’activation de la proteine C .......................................... 22 II.4.2. Place des outils de protéomique dans la mise en évidence de nouvelles cibles thérapeutiques ....... 23 II.4.3. Thérapies géniques et cellulaires ..................................................................................................... 23 ACTIONS DE NEPHROPROTECTION AU COURS DU DIABETE....................................................... 25 I. PLACE DU SKK DANS LA NEPHROPATHIE DIABETIQUE ................................................................ 26 I.1. Blocage du système renine-angiotensine et bradykinine....................................................................... 26 I.1.1. Inhibiteurs de l’enzyme de conversion ............................................................................................ 26 I.1.2. Antagonistes du recepteur AT1 de l’angiotensine II........................................................................ 28 I.1.3. Conséquences du blocage du SRA au cours de la néphropathie diabétique..................................... 29 I.1.3.1. Blocage du SRA ........................................................................................................................ 29 I.1.3.2. Mise en jeu du SKK................................................................................................................... 29 I.1.4. Activation du RB2 et néphropathie diabétique ................................................................................ 30 I.1.4.1. Arguments étayant le rôle protecteur de la BK.......................................................................... 30 I.1.4.2. Mécanismes de l’effet néphroprotecteur.................................................................................... 32 I.1.5. Et le RB1 ?....................................................................................................................................... 34 I.2. Contribution personnelle : place du recepteur B2 dans les effets du blocage du SRA au cours de la nephropathie diabétique expérimentale................................................................................................................. 36 II. ŒSTROGENES ET NEPHROPATHIES ............................................................................................... 38 II.1.1. Recepteurs nucléaires et facteurs de transcription ........................................................................... 38 II.1.2. Recepteurs membranaires................................................................................................................ 39 2 Sommaire II.1.3. Autres effets ER-indépendants des œstrogènes ............................................................................... 39 II.2. Mécanismes du rôle nephroprotecteur potentiel des œstrogènes........................................................... 40 II.2.1. Localisation dans les cellules rénales............................................................................................... 40 II.2.1.1. Localisation des recepteurs aux œstrogènes ............................................................................. 40 II.2.1.2. P450-aromatase ........................................................................................................................ 41 II.2.2. Expression génique induite dans le rein par les œstrogènes............................................................. 42 II.2.2.1. Actions génomiques des œstrogènes ........................................................................................ 42 II.2.2.2. Expressions géniques induites dans le rein par les œstrogènes................................................. 43 II.2.3. Effets des œstrogenes sur la structure du rein.................................................................................. 44 II.2.3.1. E2 et glomérule ........................................................................................................................ 44 II.2.3.2. E2 et compartiment tubulo-interstitiel...................................................................................... 46 II.2.3.3. E2 et microcirculation .............................................................................................................. 47
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