2017AlghadbanSTPhD.pdf (12.98 MB)
The Production and Use of Transgenic Mouse Models to Study the Role of Complement Pathway Activation in Progressive Kidney Disease
thesisposted on 2017-07-10, 09:57 authored by Samy Taha Abdo AlGhadban
The complement system mediates inflammatory diseases, including kidney disease, through one or more of three pathways named the classical, the alternative and the lectin pathway. The existing experimental data do not allow comprehensive understanding of the individual complement pathway or pathways that mediate the renal injury. This study therefore aimed to determine the complement pathway(s) that are involved in mediating the injury in three models of kidney disease: protein overload proteinuria, unilateral ureteric obstruction nephropathy and adriamycin nephropathy. In protein overload proteinuria, a highly significant increase in the expression levels of TGF-β, TNF-α and IL-6 was observed in WT mice compared to the lectin pathway deficient mice. Macrophage infiltration, apoptosis and the expression of the gene for Col4α1 were also significantly increased. These data suggested a significant role for the lectin pathway in mediating the injury. Most interestingly, the results indicated that antibody mediated inhibition of the lectin pathway led to less injury in some of the examined parameters. These data might suggest a novel therapeutic approach to relief the renal injury in proteinuric nephropathies by targeting the activation of the lectin pathway. In unilateral ureteric obstruction nephropathy, results indicated that deficiency in either the lectin or the classical pathways led to reduced macrophage infiltration and renal fibrosis. The expression levels of Il6, Ifn-γ, TGFβ-1 and Col4α1were reduced in the lectin pathway deficient mice but not in C1qKO mice when compared to WT. However, lower expression levels of these genes were not up to statistical significance. These data suggested that both the lectin and the classical pathways mediate the injury. Similarly, adriamycin nephropathy mice deficient in the lectin pathway showed significant reduction in renal inflammation and fibrosis when compared to WT mice. Additionally, two gene targeting approaches were utilized in order to establish a novel mouse line with specific deficiencies of both the lectin and the classical pathways of the complement. This mouse model should provide a powerful tool to investigate the possible synergetic cooperation between these two pathways in mediating inflammatory renal pathology.
Supervisor(s)Brunskill, Nigel; Schwaeble, Wilhelm
Date of award2017-06-30
Author affiliationDepartment of Infection, Immunity and Inflammation
Awarding institutionUniversity of Leicester