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Publication Detail
Investigating the role of myeloperoxidase as a key mediator of renal damage in crescentic glomerulonephritis and renocardiac disease
  • Publication Type:
    Thesis/Dissertation
  • Authors:
    Antonelou M
  • Date awarded:
    28/07/2020
  • Awarding institution:
    UCL (University College London)
  • Language:
    English
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.
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