Abstract
dc:description.abstractGlomerulosclerosis is a feature of many chronic kidney diseases. Glomeruli are composed of glomerular endothelial cells (GECs), podocytes (PODs) and mesangial cells (MCs), and dysregulation in the interaction between these cell types results in glomerulosclerosis. This is characterised by excessive extracellular matrix deposition and cell dysfunction leading to disproportionate MC proliferation and POD loss. Animal models of glomerulosclerosis often do not reflect disease pathophysiology and 2D glomerular cell monocultures provide limited insight into a disease in which cellular crosstalk and interaction are fundamental. This thesis describes a 3D tri‐culture model in which GECs, PODs and MCs are co-cultured in a collagen matrix and used to model human glomerulosclerosis with the treatment of TGF‐β. Fibrosis is replicated in the 3D tri‐culture model with nodule formation and upregulated fibrotic/inflammatory‐associated gene expression. Whilst many cytokines were identified as playing a role in the development of fibrosis in the 3D tri‐culture, TGF‐β and CTGF were demonstrated as key inducers of fibrosis. With a synergistic relationship, both cytokines required targeting for successful attenuation of fibrosis. Direct targeting of TGF‐β is impractical due to its varied and systemic modes of action. Integrin αvβ8 activates LTGF‐β to TGF‐β, and inhibition of αvβ8 proved to reduce TGF‐β evoked fibrosis in the 3D tri‐culture model. This thesis concludes that the intimate interaction of glomerular cells both physically and via signalling mechanisms in the 3D tri‐culture model mimic the in vivo state both morphologically and pathophysiologically. This is required for successful study, identification and assessment of potential therapeutic targets of glomerulosclerosis.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2021
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Sewell, Yvonne
- Advisors dc:contributor.advisor
-
- Bradley, John
- Moreno Quinn, Carol
Subjects
dc:subject × 6Rights
dc:rightsIdentifiers
dc:identifier.*- Author Identifier
-
0000-0002-8931-7420
0000-0002-7774-8805 - OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/324245