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Title: Glomerular disease : an investigation of gene expression in single human glomeruli
Author: Hall, Leon Lorenzo
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1998
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Glomerular disease commonly presents with microscopic haematuria. Holes must be present in the glomerular basement membrane to allow erythrocytes through to the urinary space. The development of these holes possibly involves the decreased synthesis and/or increased degradation of the glomerular basement membrane. Glomerulosclerosis may be viewed as the reverse scenario to that of haematuria involving the increased synthesis and decreased degradation of the mesangial matrix. In this study semi-quantitative RT-PCR based methods have been applied to single glomeruli from IgA nephropathy, thin membrane disease, and control cases. The results of these studies found decreased levels of mRNA for PDGF, MT1-MMP, TIMP1, TIMP2, and collagen type IV 2 (p values equaled 0.0026, 0.0013, 0.0119, 0.0438, and 0.015 respectively) in thin membrane disease. In IgA nephropathy decreased levels of mRNA for MT1-MMP (p=0.007) were detected. Increased mRNA for TIMP1 was seen only in IgA cases with time dependent increases in serum creatinine levels (p=0.0106). The immunocytochemistry investigation of MMP2, MMP9, collagen type III, and tenascin found increased levels of tenascin in IgA nephropathy (p=0.004). In situ zymography was used for the detection of matrix metalloproteinase activity in frozen sections. This investigation identified a 15 % decrease in metalloproteinase activity in IgA nephropathy cases. The finding of decreased MT1-MMP and TIMP1 mRNA in IgA nephropathy possibly relates to the decreased activation of MMP2 and increased inhibition of MMP9, respectively. These findings along with increased levels of tenascin protein support the proposed involvement of an imbalance in matrix synthesis and degradation as a cause of the accumulation of mesangial matrix in IgA nephropathy. Decreased levels of PDGF, MT1-MMP, TIMP1, TIMP2, and collagen type IV 2 mRNA in thin membrane disease suggest the involvement of a complex mechanism of disease involving decreased synthesis and increased degradation of the glomerular basement membrane.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available