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Genetically Modified Macrophages and Renal Regeneration

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Genetically Modified Macrophages and Renal Regeneration Genetically Modified Macrophages and Renal Regeneration Chrysoula Mastora ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) y a través del Repositorio Digital de la UB (diposit.ub.edu) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR o al Repositorio Digital de la UB. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR o al Repositorio Digital de la UB (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service and by the UB Digital Repository (diposit.ub.edu) has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized nor its spreading and availability from a site foreign to the TDX service or to the UB Digital Repository. Introducing its content in a window or frame foreign to the TDX service or to the UB Digital Repository is not authorized (framing). Those rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. Tesis doctoral Genetically Modified Macrophages and Renal Regeneration Chrysoula Mastora Departamento de Fisiología e Inmunología de la Facultad de Biología Programa de Doctorado de Fisiología Genetically Modified Macrophages and renal regeneration Tesis doctoral presentada por Chrysoula Mastora para optar al grado de Doctor por la Universidad de Barcelona Realizada en el Departamento de Isquemia e Inflamación IIBB-CSIC-IDIBAPS Directoras: Tutor: Doctoranda: Dra. Teresa Carbonell Camos Prof. Luis Palacios Raufast Chrysoula Mastora Dra. Anna Sola Martínez Barcelona, Septiembre de 2013 A mi familia ACKNOWLEDGEMENTS Me gustaria mostrar mi agradecimiento a todos los que me han acompañado durante estos ultimos cuatro años y han contribuido de una manera u otra a realizar esta tesis. En primer lugar doy las gracias a mis directoras de tesis Anna Sola y Teresa Carbonell por haber me introducido en el mundo de la ciencia, por haber confiado en mi y por haberme ayudado realizar este trabajo siempre con optimismo y mucha ilusion. Gracias a Luis Palacios, tutor de esta tesis por su ayuda y sus consejos. Gracias a la Dra Gina Hotter, que me ha aceptado en su laboratorio y que ha conseguido mantenerme aqui despues de perder la primera beca cuando todo pintaba mal. Se lo agradezco mucho. Muchisimas gracias a todos los compañeros del laboratorio por alegrarme la vida estos ultimos años. A Albert y sus unicornios a Jose y sus cervezas. A Eugenia y a Angeles por compartir tantos buenos momentos. Y claramente a Marina que ha sido una muy buena compañera dentro y fuera del laboratorio y que siempre me acompañaba en mis cafes eternos. Muchas gracias a Michaela por tenerla como amiga durante los ultimos años y por convencerme a empezar otra vez con la investigacion. A toda la gente de la sexta y septima planta por las infinitas horas en la cantina, por acogerme tan bien y hacerme sentir como en mi casa. Gracias a Nacho que siempre nos alegraba las tardes con sus historias divertidas. Muchas gracias al grupo del los Pons (Laura, Blanca, Toni, Anghara) porque despues de haberme quedado casi sola en el laboratorio, me adoptaron!! Gracias al grupo de la cantina (Sara, Leticia, Nair, Bego) por haber compartido conmigo muchisimos buen momentos y por seguir compartientolos en el futuro. Gracias al Mohamet, Eirini, Emma y Carlos por su amistad y por los pastelitos deliciosos tunecinos. Muchas a mis compis de piso Ofelia y Toña. Sin ellas seria imposible!!Y a Jordi y sus cervecitas recuperadoras! Muchas gracias a todos! Me siento muy afortunada por haberos conocido!!! Barcelona Septiembre de 2013 ABBREVIATIONS......................................................................................................... iii INTRODUCTION……………………………………………………………………………………………….…...…1 1.1 HE KIDNEY……………………………………………………….………………………………………..…….….3 1.1.1Kidney structure and organization…………………………………………………….…..3 1.1.2The nephron………………………………………………………………….………………………5 1.2 RENAL FAILURE……………………………………………………………………………….…………….…….6 1.3 ISCHEMIA/REPERFUSION……………………………………………………………….…..………….……8 1.3.1 Physiopathology of renal damage………………………………………………...………9 1.3.2 Phases of Ischemia/Reperfusion …………………………………………………….…….10 1.4 MACROPHAGES……………………………………………………………………………………………….….11 1.4.1.Origin of macrophages…………………………………………………………..……….……12 1.4.2 Macrophage phenotypes and inflammation………………………………….….…14 1.4.3 Macriphages and tissue repair……………………………………………………………..18 1.5 INFLAMMATION ASSOCIATED TO RENAL I/R…………………………………………………..….19 1.5.1 Renal Inflammation and Macrophages…………………………….…………….…….22 1.5.2 Inflammatory mediators…………………………………………………….………….…….24 1.6 RENAL REGENERATION AND ISCHEMIA / REPERFUSION……….…………………………..25 1.6.1 Regeneration markers……………………………………………………………….…….…..26 1.6.2 Genes upregulated during regeneration depending of macrophages and or cytokines……………………………………………….…………………………………….……27 1.7 Micro RNAs………………………………………………………….……………………………………….……28 1.8 PROTEASOME……………………………………………………………………………………………….…..30 1.9 IVNS1ABP……………………………………………………………….…………………………………….……32 1.9.1Stabilization of actin skeleton…………………………….…………………………….….33 1.9.2 Ivns1apb/c-myc association…………………………………………………………….….34 HYPOTHESIS AND OBJECTIVES………………………………………………………….…………………...39 MATERIALS AND METHODS…………………………………………………………….……………………..43 3.1. EXPERIMENTAL MODELS……………………………………………………………………….………...43 3.1.1. Models Description…………………………………………………………..…………….….43 3.1.2.Ischemia/Reperfusion surgical procedure………………………..……………….…43 3.1.3.Sample collection………………………………………………………………………..….…..44 3.1.4.Macrophage depletion / macrophage administration …………………………44 3.1.5.Femur extraction procedure …………………………………………………………...….45 3.2. CELL CULTURES……………………………………………………………………………………….……..…46 3.2.1 Bone Marrow Derived Macrophages (BMDMs) culture……………………...46 3.2.2 RAW 264.7 culture…………………………………………………………………………......46 3.2.3 NRK-52e culture…………………………………..…………………………………….……....46 3.2.4 NRK-52e damage assay…………………………………………………………….………...47 3.2.5 RAW 264.7/NRK-52e co-culture..............................................................47 3.3. STUDY GROUPS....................................................................................................48 Study 1: Identification of genes implicated in renal regeneration after Ischemia / Reperfusion and related to macrophages.....................................................................48 i Study 2: Role of Ivns1abp gene in the modulation of the inflammation and renal repair……………………………………………….......................................................................…...48 Study 3: Regulation of the transcription of the Ivns1abp gene...............................................................................................................................49 3.4. CELLULAR TRANSFECTION......................................................................................50 3.4.1. Adenoviral vectors ...................................................................................50 3.4.2. Adenoviral transfection............................................................................50 3.4.3. Mir-9 transfection.....................................................................................51 3.5. BIOCHEMICAL DETERMINATIONS...........................................................................52 3.5.1 Protein concentration................................................................................52 3.5.2. Creatinine and BUN levels........................................................................52 3.6. HISTOLOGY..............................................................................................................52 3.6.1 Hematoxylin and Eosin stain.....................................................................52 3.6.2 Immunofluorescence.................................................................................53 3.7.. QRT-PCR.................................................................................................................54
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