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Title: The role of local complement factor H production in complement-mediated renal disease
Author: Vernon, Katherine Anne
ISNI:       0000 0005 0734 0056
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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The aim of my research was to define the roles of local and hepatic-derived factor H, in particular the contribution of extra-hepatic factor H to plasma C3 regulation and spontaneous renal disease associated with factor H deficiency. Factor H is the major soluble regulator of the alternative pathway of complement activation, synthesised predominantly by the liver. To investigate the role of extra-hepatic factor H, I generated mice with hepatocyte-specific factor H deficiency (hepatocyte-Cfh-/-) by intercrossing conditional factor H-deficient animals with mice expressing Cre recombinase under the control of the murine albumin promoter. Plasma factor H levels in hepatocyte-Cfh-/- mice were 19% of wild-type levels and were associated with a secondary reduction in plasma C3 levels. Higher plasma C3 levels than in Cfh-/- animals demonstrated that extra-hepatic factor H contributes to plasma C3 regulation, confirmed by tubulointerstitial C3 staining in hepatocyte-Cfh-/- mice. Extra-hepatic factor H prevented the GBM C3 deposition typical of complete factor H deficiency and was associated with spontaneous mesangial C3 deposition. To test the hypothesis that underlying dysregulation of the alternative pathway predisposes to exaggerated renal injury in the presence of additional complement activation, I assessed the response of hepatocyte-Cfh-/- mice to accelerated serum nephrotoxic nephritis. Injection of nephrotoxic serum led to the rapid onset of haemolytic uraemic syndrome. Subtotal deficiency of factor H in hepatocyte-Cfh-/- mice therefore provides a novel model of either C3 glomerulopathy or atypical haemolytic uraemic syndrome depending on the environmental milieu. This mouse model will enable the pathophysiological mechanisms involved to be further defined and new therapeutics investigated. I also examined the association between abnormalities in factor H-related protein 5 and C3 glomerulopathy. Minimal expression of normal factor H-related protein 5 within the kidney could not prevent CFHR5 nephropathy. Serum factor H-related protein 5 levels may be a marker of renal complement deposition.
Supervisor: Pickering, Matthew ; Botto, Marina Sponsor: Kidney Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral