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The role of thymosin beta 4 in renal podocyte function

Mason, William John (2021) The role of thymosin beta 4 in renal podocyte function. Doctor of Philosophy (PhD) thesis, University of Kent,. (doi:10.22024/UniKent/01.02.89494) (KAR id:89494)

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Official URL:
https://doi.org/10.22024/UniKent/01.02.89494

Abstract

Ten percent of the world have chronic kidney disease (CKD). In some patients, CKD can be catastrophic, leading to end stage kidney disease (ESKD), requiring lifelong dialysis or kidney transplant. Identification and analysis of molecules that can halt the progression of CKD to ESKD has the potential to save lives. The glomerulus is the site of the kidney, where the blood is filtered to produce urine. The glomerular filtration barrier consists of endothelial cells, a basement membrane and podocytes, epithelial cells with a unique shape maintained by the actin cytoskeleton. Damage to the structure of podocytes, is a significant contributing factor to CKD progression, and disorganisation of the podocyte cytoskeleton is a key factor associated with podocyte damage. Thymosin \(\beta\)4 (TB4) is the major G-actin sequestering molecule in mammalian cells and it regulates cell morphology, inflammation, and fibrosis. TB4 has beneficial effects in rodent models of kidney injury, including protection of the glomerulus, but the effect of exogenous TB4 on podocytes is currently unknown. The aim of this thesis was to examine the effect of exogenous TB4 in cytotoxic and immune mediated podocyte injury models. Podocyte injury induced by the toxin Adriamycin (ADR) resulted in downregulation of the mRNA transcript for TB4 in podocytes. Examination of the F-actin cytoskeleton in mouse immortalised podocytes by phalloidin staining demonstrated that exogenous TB4 completely prevented ADR-induced F-actin disorganisation in vitro, a key factor in glomerular filtration barrier damage in vivo. The effect of exogenous TB4 was then examined in ADR nephropathy and nephrotoxic serum (NTS) nephritis in mice. Systemic upregulation of TB4 was achieved by recombinant adeno associated virus (AAV) mediated gene delivery prior to disease induction. Exogenous TB4 prevented damage to the glomerular filtration barrier, shown by reduced urine levels of albumin, in ADR nephropathy and early NTS nephritis. This was most likely due to prevention of podocyte loss, protection of glomerular F-actin in ADR nephropathy, and suppression of inflammation in NTS nephritis, as determined by light and fluorescent microscopy. In summary, this thesis has provided strong evidence that exogenous TB4 is a beneficial molecule in the context of glomerular and podocyte injury. In the future, it is hoped that use of exogenous TB4 can translate to human physiology and be developed as a therapeutic strategy to alleviate the progression of CKD to ESKD.

Item Type: Thesis (Doctor of Philosophy (PhD))
Thesis advisor: Vasilopoulou, Elisavet
Thesis advisor: Peppiatt-Wildman, Claire
Thesis advisor: Long, David Andrew
DOI/Identification number: 10.22024/UniKent/01.02.89494
Uncontrolled keywords: Kidney; podocyte; cytoskeleton; thymosin beta 4; TB4; glomerulus; f-actin; gene therapy
Subjects: R Medicine > R Medicine (General)
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
SWORD Depositor: System Moodle
Depositing User: System Moodle
Date Deposited: 28 Jul 2021 13:10 UTC
Last Modified: 04 Aug 2021 07:14 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/89494 (The current URI for this page, for reference purposes)
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