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Title: Tissue transglutaminase in human and experimental diabetic nephropathy
Author: Skill, Nicholas James
ISNI:       0000 0001 3416 6517
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2001
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Tissue transglutaminase (tTg) is a multifunctional enzyme and is implicated in numerous cellular and extracellular events, these include cell growth and differentiation, receptor mediated endocytosis, cell adhesion, and cell death. In particular tTg has been linked to the accumulation of extracellular proteins due to its ability to form proteolytic resistant ε-(γ glutamyl)lysine bonds. Previous work has implicated tTg in fibrosis of numerous tissues, these include lung, liver, heart and in particular kidney. Diabetic nephropathy (DN) is the most common cause of end stage renal failure (ESRF) in the western world and accounted for 42% of all new cases of ESRF in the USA in 1997. It occurs in approximately 40% of patients with type I diabetes (IDDM) and is characterized by the thickening of the glomerular and tubular basement membranes and the expansion of the mesangial and tubulointerstitial matrix. Interestingly, a recent finding has shown that 40% of patients with type I diabetes mellitus have auto antibodies to tTg. In this thesis changes in tTg have been investigated using the subtotal nephrectomy (SNx) model of acute renal fibrosis, the streptozotocin (STZ) induced hyperglycaemia model, human biopsy sections taken from diseased kidneys and in vitro experiments using opossum kidney proximal tubule epithelial cells. In accordance with its hypothesized role in ECM accumulation tTg antigen was increased within the tubulointerstitium of diseased kidneys when compared to controls. This was also true of ε-(γ glutamyl)lysine and in situ activity. In contrast to the SNx model of renal fibrosis there was no increase in tTg mRNA, Tg activity or tTg antigen in kidney homogenates from STZ treated rats when compared to controls. However isolated glomerular fractions from STZ and control kidneys showed an increase in both Tg activity and tTg antigen. This contrast is thought to be due to the down regulation of tTg expression because of the methylation of its promoter by STZ and also because of the selective uptake of STZ due to its sugar moiety. More importantly, tTg and e(y-glutamyl)lysine was shown to be increased in numerous human nephropathies, including DN, and the degree of tTg and ε-(γ-glutamyl)lysine staining appeared to correlate with the loss of kidney function during the course of kidney rejection. In vitro experiments confirmed that hyperglycaemia can increase tTg antigen and Tg activity in epithelial cells, which results in an increase of extracellular ε-(γ-glutamyl)lysine, which coincided with an increase in extracellular fibronectin and hydroxyproline. The use of a Tg specific inhibitor not only reduced the level of extracellular ε-(γ-glutamyl)lysine but also reduced the level of hydroxyproline.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Cell; Growth; Differentiation; Adhesion; Death