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Angiopoietin Growth Factors in Models of Renal Disease

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Angiopoietin Growth Factors in Models of Renal Disease Angiopoietin Growth Factors in Models of Renal Disease by David Andrew Long A thesis submitted to the University of London in fulfilment of the requirement for the degree of Doctor of Philosophy October 2002 Nephro-Urology Unit, Institute of Child Health, University College London ProQuest Number: U644007 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U644007 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 To my Mum, Dad and Brother Abstract Angiopoietin (Ang) growth factors modulate endothelial survival and morphogenesis, actions depending on an interplay of agonistic (Ang-1) and antagonistic (Ang-2) angiopoietins with their Tie-2 receptor tyrosine kinase and vascular endothelial growth factor (VEGF) signalling through VEGF receptor 2. Emerging data suggests that Angl stabilizes capillaries. In contrast Ang2 disrupts vessels, facilitating sprouting when ambient VEGF is high but causing regression when ambient VEGF is low. My study has determined the expression of the angiopoietin family in a model of acute nephrotoxicity induced by administration of folic acid. In this model there was increased endothelial cell turnover in renal peritubular capillaries following injection of folic acid. This microvascular remodelling was accompanied by de novo expression of immunoreactive Ang-1 in regenerating distal convoluted tubules (DCT) and increased Ang-1 on western blot. This suggested a potential paracrine system between renal tubular epithelia releasing Ang and peritubular capillaries, which expressed the Tie-2 receptor in folic acid induced nephrotoxicity. I hypothesised that cytokines may regulate the expression of Ang in renal epithelia in folic acid induced nephrotoxicity. Immunostaining for macrophages, neutrophils and T-lymphocytes showed a modest increase in these cell populations in the first few days after folic acid injection. In addition, immunoreactive TNF-a was detected in the vicinity of a subset of cortical tubules, most likely DCT, from the first few days after induction of nephrotoxicity Finally, immortalised murine DCT cells were investigated. Conditioned media from DCT cells stimulated with TNF-a reduced Tie-2 phosphorylation when added to endothelial cells versus conditioned media from DCT cells with no added TNF-a. As TNF-a also decreased VEGF immunoreactivity in medium conditioned by these renal epithelia, I propose that this cytokine, which is upregulated in several experimental models of renal injury, may encourage an anti-angiogenic milieu with decreased capillary stability and microvascular regression. Hence, these in-vitro and in-vivo experiments add to the current evidence about the role of the angiopoietins in models of renal disease and also the mechanisms by which these effects are achieved. Acknowledgements My research has been a most enjoyable experience and I would like to primarily thank my two supervisors, Professor Adrian Woolf and Dr. Hai Tao Yuan for initially giving me the opportunity to start this research and their continuous support throughout my thesis. Their intellectual input, expert technical advice and guidance through all aspects of my research has been invaluable throughout the progression of this thesis and has enabled me to have the best possible start to my scientific career. In addition, I must also thank the Medical Research Council for the funding of this studentship for my research. Some of the experiments in my thesis would not have been possible without the advice of many members of the Nephro-Urology Unit at the Institute of Child Health. Special thanks go to Xiao Zhang Li for his work on the VEGF family in the folic acid model, Jolanta Pitera for developing Ang-2 immunohisotchemical protocols, Maria Kolatsi-Joannou for her general advice in developing immunohisotchemical techniques and Vanita Shah for helping to develop and perform ELISA techniques. I must also thank all of my past and present colleagues for their support throughout this thesis, not just academically but socially. A special mention goes to Paul Winyard, for his support, advice and computer expertise, Karen Price and Shuman Haq for managing to put up with me working next to me in the laboratory and Simon Welham for his extensive ideas and general enthusiasm. Further thanks go to Marlene Attard, Tanya Johnson, Liam McCarthy, Layla Romio, Naima Smeulders and Niki Thiruchelvam for their general help and comments. On a personal note, I would like to take this opportunity to thank my family at home for all of their support throughout this thesis. Abbreviations aa amino acid Ang angiopoietin ARF acute renal failure ATN acute tubular necrosis BCA bicinchoninic acid bp base-pair BSA bovine serum albumin cm centimetre cDNA complementary deoxyribonucleic acid DAB diaminobenzidine DCT distal convoluted tubule DEPC diethylpyrocarbonate DMEM dulbecco’s modified eagle medium DMSO dimethyl sulfoxide DNA deoxyribonucleic acid E embryonic day ECL enhanced chemiluminescence EDTA ethylenediaminetetraacetic acid EGTA ethylene glycol-bis-N, N, N% N ’-tetracetic acid ELISA enzyme-linked immunosorbent assay FA folic acid PCS fetal calf serum g gram GBM glomerular basement membrane HRP horseradish peroxidase IL-lp interleukin-Ip Kb kilobase KDa kilodalton Kg kilogram L litre LDH lactate dehydrogenase M molar i.e. concentration in moles per litre kig microgram Hi microlitre |im micrometre ml millilitre mV millivolts MOPS 3-N-morpholinopropanesulfonic acid mRNA messenger ribonucleic acid n number ng nanogram nm nanometre nt nucleotide PBS phosphate buffered saline PCNA proliferating cell nuclear antigen PECAM platelet endothelial cell adhesion molecule PMSF phenylmethylsulfonyl fluoride RNA ribonucleic acid RT-PCR reverse-transcription polymerase chain reaction SEM standard error mean SSC sodium chloride-sodium citrate SSPE saline-sodium phosphate EDTA TAE tris-acetate-EDT A TGF-P transforming growth factor-P TNF-a tumour necrosis factor-a VEGF vascular endothelial growth factor xg X gravity Contents Acknowledgements ................................................................................................................ 5 Abbreviations ..........................................................................................................................6 List of Figures ...................................................................................................................... 14 Introduction .......................................................................................................................... 18 Introduction .......................................................................................................................... 18 Aim of this Thesis ....................................................................................................................... 18 Hypotheses ..................................................................................................................................18 Overview.....................................................................................................................................19 Chapter 1: The anatomy of renal blood vessels ........................................................20 General Characteristics............................................................................................................. 20 The Blood Vessels of the Kidney ................................................................................................22 The Nephron .............................................................................................................................. 23 The Glomerulus .......................................................................................................................26 The Blood Supply of the Tubules .............................................................................................28 Chapter 2: Vascular Growth Factors ...........................................................................31 The Tie Receptor Kinase Family ...............................................................................................32 The Tie Receptors ....................................................................................................................32 The Angiopoietins - Ligands for the Tie-2 Receptor ................................................................ 35 Alternative Splicing of the Angiopoietins ................................................................................ 37 Downstream Targets of the Ang/Tie Family ............................................................................ 40 Expression of the Angiopoietins ...............................................................................................43 Expression of Angiopoietins in Embryos and Mature Kidneys .................................................44 The Regulation of Angiopoietin Expression ............................................................................. 47 Vascular Endothelial Growth Factor
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