Renal tubulointerstitial fibrosis is a major predictor of progressive
glomerular disease. It occurs as a result of persistent
inflammation and is characterised by excessive deposition of
extracellular matrix (ECM) proteins, including accumulation of
type I collagen, the most abundant protein of the ECM.
Type I collagen is encoded by two genes, COL1A1 and COL1A2,
that are tightly regulated at a transcriptional level. A key aim of
this study was to use the previously identified COL1A2 promoter
and enhancer sequences in order to identify novel regulatory cis-acting
elements and the relevant transcription factors that
regulate collagen transcription in cells derived from healthy or
diseased kidneys. Moreover, the effects of hypoxia and
transforming growth factor beta (TGFβ), which are both profibrotic
stimuli, on collagen transcription were studied. TGFβ is
known to activate CDP/cux transcription factors which can
suppress gene activation; based on this finding the role of
CDP/cux in COL1A2 transcriptional regulation was assessed.
In conclusion,the work presented in this thesis provides an
insight into the complex control mechanisms that regulate
collagen transcription in both physiological and pathological
conditions.