Despite advances in its management, diabetic nephropathy continues to be the leading cause of end-stage kidney disease. Hyperplasia, hypertrophy, and extracellular matrix expansion are known to be present at the early stages of disease development, suggesting that a better understanding of the associated molecular mechanisms may point to novel therapeutic targets. The aim of this thesis was to investigate the mechanism and regulation of proliferation and cell growth in a cell culture model. In particular, the effects of metformin and rapamycin on the AMPKlmTORC1 signalling pathway were studied in mechanisms associated with the diabetic kidney. The results indicate that high ambient glucose differentially modulate the effects of metformin and rapamycin on mTORC1-related parameters related to proliferation and cell growth. These effects of high glucose have been associated with reduced AMPK activation. It has also been revealed that metformin and high glucose have an inverse relationship in the regulation of p21 CIP1N'JAF\ a cell cycle regulatory protein implicated in kidney hypertrophy, replicative senescence, and cancer. The results show that metformin inhibits proliferation and the expression of p21CIP1M1AFl in an AMPKa2-dependent manner. Metformin induced GO/G1 arrest and the associated down-regulation of p21 correlated with the level of cyclin D1, while rapamycin inhibited cell cycling without having an effect on these cell cycle regulators. These findings challenge the dogmatic view of p21clP1NVAF1 as a cell cycle inhibitor and may have relevance to the mechanism of high glucose-induced hyperplasia that precedes hypertrophic changes in the diabetic kidney. Several studies have linked increased GLUT1 expression to glomerular hypertrophy. However, despite increased cellular growth and extracellular matrix production, high glucose down-regulated GLUT1 expression in human mesangial cells in this study. Contrary to the general view; these findings suggest that in human mesangial cells a protective mechanism may operate against the harmful effects of hyperglycaemia.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:590665 |
| Date | January 2013 |
| Creators | Molnar, Zoltan |
| Publisher | Exeter and Plymouth Peninsula Medical School |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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