Abstract
Chronic kidney disease (CKD) is a substantial global health concern, impacting 10-15% of the world’s population. CKD increases the risk of hospitalisation, co-morbidity and mortality, and ultimately reduces patient quality of life. Renal fibrosis, and the structural and functional changes that accompany it, is a key step in the pathogenesis of CKD. Intriguingly, the effects of CKD are not limited to the renal system; with muscle wasting common in CKD, which synergistically causes debilitation and reduced patient quality of life. It is necessary to identify new therapeutic targets that effectively ameliorate CKD development and progression, such as those that target renal fibrosis and muscle wasting. Upregulated Activin A, a growth and differentiation factor, has been identified in CKD and CKD-induced muscle wasting. Whilst inhibiting Activin A successfully ameliorates renal fibrosis and muscle wasting in vivo, understanding of its signalling pathways remains elusive, particularly in renal proximal tubule epithelial cells and in endoplasmic reticulum (ER) stress pathways in skeletal muscle cells which may contribute to muscle wasting.This thesis aims to characterise the expression and activity of Activin A in kidney pathophysiology during CKD in proximal tubule cells and the unfolded protein response (UPR) in skeletal muscle cells, a signalling pathway which contributes to muscle wasting.
The data presented in this thesis is one of the first studies to investigate the role of Activin A signalling specifically in human-derived renal proximal tubule cells, a key cell population important in CKD development and progression. It demonstrates an important role of Activin A in proximal tubule cells in response to TGFβ, and also identifies a novel effect on skeletal muscle UPR which may have implications in the understanding of CKD-induced muscle wasting.
| Date of Award | 2024 |
|---|---|
| Original language | English |
| Awarding Institution |
|
| Supervisor | Kayte Jenkin (Supervisor) & Ben Perry (Supervisor) |