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Title: Role of P2X7-mediated inflammasome activation in glomerulonephritis
Author: Deplano, Simona
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Glomerulonephritis is a major cause of kidney failure and current treatment is based on nonspecific immunosuppressive therapies. The purinergic P2X7 receptor (P2X7R) is usually not detectable in renal tissue. However, previous studies have demonstrated an increased glomerular P2X7R expression in animal models of glomerulonephritis. Furthermore, P2X7R knock-out mice have been shown to be significantly protected from antibody-mediated glomerulonephritis. P2X7R activation represents a fundamental step for the activation of the NLRP3 inflammasome which leads to the processing and release of IL-1β and IL-18. The role of the inflammasome activation in glomerulonephritis is not clear yet. The work presented in this thesis describes three aspects of P2X7R activation: cytokine production, signalling cascade following ATP stimulation and inflammasome activation. My data show that macrophages from wild type mice produce higher levels of IL-1β and IL-18 compared to macrophages from P2X7 deficient mice. ATP stimulation activates several signalling pathways in macrophages. Among them, the ribosomal pathway appears to be strictly regulated by P2X7R. To investigate the role of the inflammasome activation in glomerulonephritis I have compared macrophages from the susceptible rat strain Wistar-Kyoto with macrophages from the resistant strain Lewis. WKY macrophages express higher P2X7 mRNA and protein levels, release higher levels of IL-1β and IL-18 and exhibit a greater caspase-1 activity. Similarly, WKY nephritic glomeruli show higher P2X7, IL-1β, IL-18 and caspase-1 levels compared to Lewis glomeruli. Finally, in the attempt to identify genes responsible for the inflammasome regulation, I have examined macrophages and nephritic glomeruli from congenic rats. My data seem to indicate that the susceptibility locus Crgn2 contains one or more genes that control IL-1β and IL-18 release in macrophages. Further studies are certainly required to verify the relevance of these data. The results are important in understanding the pathogenesis of glomerulonephritis and identification of new potential therapeutic targets.
Supervisor: Tam, Frederick Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available