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The role of hyaluronan and its receptors in the acute kidney injury to chronic kidney disease continuum

Brown, Charlotte 2021. The role of hyaluronan and its receptors in the acute kidney injury to chronic kidney disease continuum. PhD Thesis, Cardiff University.
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Ischaemia reperfusion injury (IRI) results in acute and chronic kidney damage. Ischaemic preconditioning (IPC) is a brief period of ischaemia, which reduces IRI by unknown mechanisms. Delineating IPC mechanisms could identify novel mediators that limit kidney damage. Hyaluronan (HA) is a matrix glycosaminoglycan that demonstrates increased expression in renal damage, correlating with outcomes. This research aimed to investigate if alterations in HA and its associated binding-proteins mediated IRI-damage and/or IPCmediated protection. A rat model of bilateral renal IRI and IPC was developed from AKI to CKD. Rat kidneys were assessed at 24h, 48h, 7d, 14d and 28d for histological changes and RNA analyses (RT-qPCR and total RNA-sequencing). IRI led to marked histological damage, with increased expression of key fibrotic mediators at all time-points. Acutely, HA generation was hyaluronan synthase 2 (HAS2) dependent; HAS2 was more inducible in this model and found in the interstitium on immunohistochemical analysis, in the same areas as HA generation. HAS1 was found in a subset of tubular epithelial cells, not associated with HA generation at 48h. HAS2 and CD44 (HA-receptor) expression was attenuated by IPC. However, a CD44 variant, CD44v7/8, previously associated with an antifibrotic phenotype in-vitro, was upregulated by IPC and found on the basolateral membrane of HAS1 positive tubular epithelial cells. Gene Set Enrichment Analysis (GSEA) demonstrated enrichment of HA-related genes in IRI at all time-points and negative enrichment in IPC. GSEA also demonstrated enrichment of DNA repair and angiogenesis pathways at 14d, a potential key transition point. This work demonstrated that IPC prevented both acute and chronic IRI-damage. The relationship between HA generation and HA expression was altered with IRI and IPC, with HAS isoforms and CD44 variants being differentially expressed. This suggests an integral link between HA and its receptors in the AKI to CKD continuum and their role in IPC.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 20 September 2021
Last Modified: 20 Sep 2021 10:18

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