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This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Endothelin‐1 antagonism in glomerulonephritis Elizabeth Louise Owen BSc. (Hons), MSc. A thesis submitted towards the degree of PhD The University of Edinburgh 2016 Declaration I declare that the work presented in this thesis is my own and has not previously been published or presented towards another higher degree except where clearly acknowledged as such in the text. ……………………………………… …………. Elizabeth Louise Owen Date Page | 2 Acknowledgements I would like to express my gratitude to my supervisor David Kluth for his support, guidance and efforts during my PhD; Bean, thankyou for your patience and input. Thankyou also to Jeremy Hughes and Simon Brown for your advice and input for the various aspects of labwork, presentations and general how to’s. Jason King, thanks for all your help in the lab, you were always my ‘go‐to‐guy’ for all things technical….and for your many cool pairs of trainers. The rest of the PIG lab‐ Katie Mylonas, Jillian Rennie, Katherine Miles, Davis Vass, Matt Beesley and Madeline Vernon, a sincere thankyou for all the lab nights out and help and support. A big thankyou to Matt Bailey and Spike Clay, and John and Willie for all their hard work with the animals and in ex vivo. Also to Shonna Johnston and Fiona for their hard work and support in the flow lab. To Catherine and Madhavi‐ thankyou and well done for being hardworking diligent students. Certain other friends and family also deserve a special mention; Yvonne Nelson‐ years spent together in the QMRI, many long crazy days and nights navigating youth together, the occasional youtube ABBA video and drunken nights proved for the forging of a lifelong friendship. Madina, Jonathan and Dave.. those papers never did read themselves, but we muddled through!! Ekin Bolukbassi‐ without you and Demis Roussos I’m not sure I would have made it through! James Catterson‐ alreet pal…thanks for being good friends….the lunchbreak chats and nights out will remain forever in my heart and mind. Andy and Greig Mackie, thankyou for dealing with me through all our life dramas. Thankyou to my oldest friend Charlotte… We’ve had many years of life to contend with together and apart. Sometimes we break up, but we always make up. No matter how much time passes without seeing you, when we come back together its like we’ve never been apart. Thankyou for being a true friend who is a part of my past and present and will undoubtedly be an integral part of my future. To Dr Gandy… the time has come to break out the popping candy and sloe gin. Thankyou for showing me the light at the end of the tunnel! Finally, my family‐ my siblings and parents who have always done the best they can through difficult times, thankyou for all your support over the years. I would also like to express my gratitude to Kidney Research UK for funding this work. Page | 3 Table of Contents Endothelin‐1 antagonism in glomerulonephritis ....................................................... 1 Declaration ...................................................................................................................................... 2 Acknowledgements ..................................................................................................................... 3 Table of Contents ......................................................................................................................... 4 Figures and Tables ...................................................................................................................... 9 Abbreviations ............................................................................................................................. 12 Abstract .......................................................................................................................................... 17 Lay Summary ............................................................................................................................... 19 Chapter 1 ....................................................................................................................................... 20 1.1 The burden of chronic kidney disease ................................................................... 21 1.1.1 Definition of chronic kidney disease 21 1.1.2 Hypertension 24 1.1.3 Epidemiology and aetiology of CKD 25 1.1.4 Progression of CKD to ESRD 26 1.1.5 Proteinuria in CKD 27 1.1.6 Preventing the progression of CKD 28 1.2 Glomerular diseases ..................................................................................................... 30 1.2.1 Normal glomerular filtration 30 1.2.2 Glomerular disease classification 33 1.2.3 Clinical presentation of glomerulopathies 34 1.2.4 Aetiology of glomerulonephritis 39 1.2.5 Pathogenesis of glomerulonephritis 39 1.2.6 Podocyte structure and function 49 1.3 Therapeutic intervention ............................................................................................ 55 1.3.1 Protecting the glomerulus from podocyte loss and effacement 56 1.3.2 The Endothelin System 61 1.3.3 Endothelins in the Kidney 62 1.3.4 Therapeutic intervention by ET receptor blockade 63 1.4 Overview ........................................................................................................................... 69 1.5 Hypothesis and Aims .................................................................................................... 70 Page | 4 Chapter 2 ....................................................................................................................................... 71 2.1 In vitro studies ................................................................................................................. 72 2.1.1 Cell Culture 72 2.1.2 ET‐1 stimulation assay 73 2.1.3 ET‐1 stability assay 74 2.1.4 ET‐1 quantification 74 2.1.5 Enzyme‐linked immunosorbent assay (ELISA) 74 2.1.6 ET receptor antagonist assays 75 2.1.7 Immunofluorescence (IF) studies 76 2.1.8 Cellular protein extraction 77 2.1.9 Total protein quantification 77 2.1.10 SDS‐PAGE and Western blot 77 2.1.11 RNA extraction and RT‐PCR 78 2.1.12 Mϕ migration assay 80 2.1.13 Mϕ phagocytosis assay 80 2.1.14 Mϕ Endocytosis assays 81 2.1.15 Mϕ protease inhibitor assay 81 2.2 In vivo studies .................................................................................................................. 82 2.2.1 Rat nephrotoxic nephritis (NTN) 82 2.2.2 Murine Mϕ depletion in CD11b‐DTR mice 88 2.2.3 Statistical analyses 100 Chapter 3 ..................................................................................................................................... 101 3.1 Introduction ................................................................................................................... 102 3.1.1 Experimental hypothesis and aims 102 3.2 Experimental protocol ............................................................................................... 103 3.3 Preliminary studies with NTN model ................................................................... 105 3.3.1 NTS treated animals develop progressive glomerulonephritis 105 3.3.2 Sitaxsentan improves renal function and glomerular inflammation 105 3.4 Selective ETAR antagonism in nephrotoxic nephritis studies ...................... 109 3.4.1 NTS treated animals develop progressive GN 109 3.4.2 STX treatment reduces hypertension 109 3.5 Selective ETA receptor antagonism in severe NTN ........................................... 113 3.5.1 NTS treated animals develop progressive proteinuria 113 3.5.2 STX improves proteinuria and blood pressure 113 3.6 Summary ......................................................................................................................... 117 3.7 Discussion ....................................................................................................................... 118 3.7.1 ETAR antagonism in experimental NTN 118 3.7.2 NTS induces progressive GN 119 3.7.3 Sitaxsentan reduces hypertension and macrophage infiltration in experimental nephrotoxic nephritis 119 3.7.4 Podocyte cell structure and function remain un‐assessed 119 3.7.5 Glomerular inflammation is reduced in STX treated NTN animals 120 3.7.6 Further Work 120 Page | 5 Chapter 4 ..................................................................................................................................... 123 4.1 Introduction ................................................................................................................... 124 4.1.1 Experimental hypothesis and aims 125 4.2 Experimental Protocol ............................................................................................... 127 4.3 Human monocyte/macrophage (Mϕ) cell culture
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