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Investigating the role of myeloperoxidase as a key mediator of renal damage in crescentic glomerulonephritis and renocardiac disease

Antonelou, Marilina; (2020) Investigating the role of myeloperoxidase as a key mediator of renal damage in crescentic glomerulonephritis and renocardiac disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Crescentic glomerulonephritis (CGN) describes a severe form of glomerular inflammation, which results from various systemic or renal specific diseases, including anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV) characterised by glomerular neutrophil and monocyte activation and neutrophil extracellular trap deposition. Diseases associated with CGN are frequently associated with increased cardiovascular disease, which represents a significant cause of premature mortality. Myeloperoxidase (MPO), a heme containing peroxidase stored in neutrophils and monocytes, is a key component of innate immune defence, generating hydrochlorous acid and free radicles that can also lead to host tissue damage. Additionally, MPO has been shown to contribute to vascular inflammation and atherosclerosis through oxidation of lipoproteins and catabolism of nitrous oxide leading to endothelial damage. In humans, MPO deficiency does not appear to lead to an immunodeficient phenotype. In this thesis, the role of selective MPO inhibition using AZM198, as a therapeutic target in CGN and associated reno-cardiac disease is explored. Our data demonstrate that free MPO levels are elevated in patients with active AAN and reduced when disease reaches remission. Renal biopsies of patients with diverse forms of CGN had extracellular glomerular MPO deposition that correlated significantly with clinical and histological disease severity. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap (NET) formation, reactive oxygen species (ROS) production and neutrophil degranulation and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment at two different doses reduced glomerular inflammation. Combining a murine model of chronic glomerular inflammation and atheroma formation showed that the presence of nephritis enhances atheroma formation. This model will be used in future work to compare treatment with AZM198 with corticosteroid therapy, currently used to treat most conditions associated with CGN.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating the role of myeloperoxidase as a key mediator of renal damage in crescentic glomerulonephritis and renocardiac disease
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10105861
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