MicroRNA-21 in diabetic nephropathy and a cross-sectional analysis of the role of TGFβ in proximal tubule epithelial cells and mesangial cells
thesisposted on 03.03.2017 by McClelland, Aaron David
In order to distinguish essays and pre-prints from academic theses, we have a separate category. These are often much longer text based documents than a paper.
Diabetic nephropathy (DN) is the leading cause of renal failure in much of the world. It is a complex disease resulting in pathological changes in various cell types and ultimately culminating in end-stage renal disease. Specifically, mesangial cells (MC) undergo hyperplasia and hypertrophy leading to destruction of the glomerular ultrastructure while also contributing to podocytes loss. Proximal tubule epithelial cells (PTC) undergo similar processes leading to tubulointerstitial fibrosis and also interstitial inflammation. Although these changes are initially propagated by chronic hyperglycaemia, the changes in cellular physiology are elicited via activation and modulation of a wide range of pathways and their products. A central and potent mediator cellular pathophysiology in diabetic nephropathy is TGFβ which is itself upregulated by hyperglycaemia. TGFβ influences many cellular processes and signalling networks. It has becoming increasingly clear that TGFβ mediates its effects in the diabetic kidney through dysregulation of microRNA particularly in MC and PTC, although the extent of these relationships has not been investigated. Despite this, there is still a lack of system biology approaches available for the study of microRNA. Also gaining attention in recent years is the role of mitochondrial dysfunction in the propagation of DN. Although links have been made between TGFβ and mitochondrial function or microRNA expression and mitochondrial function, little has been reported on the influence of TGFβ-mediated microRNA dysregulation on mitochondria. To this end, this thesis has demonstrates and explores the wide reaching effects of TGFβ upon both PTC and MC. The genome wide effect of TGFβ-mediated miRNA dysregulation of the cell wide signalling landscape is also explored. miR-21 is highly dysregulated in PTC and its role in TGFβ-mediated fibrotic signalling is clarified. This effect is clearly defined in regard to the relative contribution of SMAD7 and PTEN. The significance of miR-21 in human DN is also demonstrated. Finally, the role of miR-21 in mitochondrial dysfunction in PTC is proposed to occur at least in part through ACAT1 and AK2. This work adds valuable knowledge to the growing recognition of the importance of microRNA in DN. Furthermore, the development of in silico pipelines may aid those who endeavour to undertake similar projects with the data garnered from such experiments providing an important reference for future investigations. The findings from this thesis are likely to aid in the development of future therapies focusing on retarding the development and progression of DN, not least of all in the rectification of mitochondrial dysfunction and preventing the relentless cycle of fibrotic tissue damage that ultimately results in renal failure. Additional material(s) submitted with thesis.