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MicroRNA regulation of podocyte insulin sensitivity

Wonnacott, Alexa 2020. MicroRNA regulation of podocyte insulin sensitivity. PhD Thesis, Cardiff University.
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Abstract

Diabetic Nephropathy (DN) is a devastating complication of diabetes, and is the leading cause of end stage renal failure in the UK. Uncovering mechanistic pathways in DN pathogenesis is vital in establishing new therapeutic targets to prevent its progression. Podocyte-specific insulin resistance in mice leads to a renal injury that mimics that seen in diabetic kidney disease, indicating that podocyte insulin signalling may be of critical importance in the development of DN. MicroRNAs (miRNAs) are post-transcriptional gene regulators that demonstrate aberrant expression in multiple diabetic models, and are implicated in the development of insulin resistance in liver, fat and muscle. The aim of this work was to establish the role of miRNAs in the regulation of podocyte insulin signalling. This thesis details the differential microRNA expression of an in vitro model of podocyte insulin resistance, and the subsequent validation of miR-155-5p as an important regulator of podocyte insulin sensitivity. MiR-155 was upregulated in insulin-resistant podocytes, and in the urine of patients with DN. Furthermore, overexpression of miR-155 in podocytes resulted in reduction in PI3K/Akt signalling and abrogation of glucose uptake in vitro. Bioinformatic analyses were used to identify putative miR-155 targets. PIK3R1 and CSF1R were confirmed to demonstrate miR-155 induced repression, hypothesised to result in podocyte insulin resistance via negative regulation of PI3K signalling. Whole glomerular miRNA sequencing from the db/db mouse indicated that changes associated with established diabetic pathways of oxidative stress, inflammation and fibrosis are transcriptionally activated as early as 4 weeks. These findings support the hypothesis that changes in miRNA expression are an initiating insult in DN, and highlight miRNAs as potential therapeutic targets to arrest disease development.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 21 August 2020
Last Modified: 21 Aug 2020 14:09
URI: http://orca.cf.ac.uk/id/eprint/134314

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