Identifying novel stromal-mediated mechanisms that modify ischaemia-driven progressive renal injury

Zaidi, Aeliya 2025. Identifying novel stromal-mediated mechanisms that modify ischaemia-driven progressive renal injury. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

AKI and CKD are significant global health burdens and increasingly recognised as a continuous disease spectrum rather than distinct clinical entities. To date, no specific treatments exist for AKI-CKD. Ischaemia-reperfusion injury (IRI) is the predominant pathophysiological process underlying majority of AKI admissions. Ischaemic Preconditioning (IPC) has been shown to be protective against IRI but not successful in clinical practice. This thesis used in vivo models of kidney IRI and IPC to identify novel mediators and therapeutic targets to prevent AKI-to-CKD progression. Building on prior in vitro and in vivo evidence of hyaluronan (HA) matrix alterations, this thesis hypothesised that HA-mediated matrix changes underlie IPC’s protective effects and causally influence renal repair over fibrosis. The first results chapter showed that injured and preconditioned kidneys in a rat model are indistinguishable histologically at 14 days, however progress to fibrosis and recovery respectively by day 28. Preconditioned kidneys had reduced stromal HA, enhanced tubular HA internalisation, and increased expression of the HA receptor isoform CD44V7/8. Transcriptomic analyses at day 14 uncovered a differential expression of genes between injured and preconditioned kidneys. The second results chapter established and characterised a mouse model of bilateral IRI induced AKI-CKD, enabling evaluation of novel therapeutic strategies. HA modulation was explored in the final results chapter through two complementary in vivo strategies: chemical inhibition of HA synthesis using 4MU in the IRI mouse model, and stromal HA targeting via CD44V7/8 nanoparticle delivery in a unilateral-ureteric-obstruction (UUO) mouse model. Attenuation of injury and fibrosis were seen with both approaches, demonstrating therapeutic benefit conferred by HA modulation across distinct kidney injury models. These findings establish HA accumulation in the renal stroma as a key determinant of renal outcomes, reinforcing its role in mediating IPC-induced protection. HA modulation is a promising therapeutic avenue to mitigate AKI-to-CKD progression, warranting further translational investigation.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	26 May 2026
Last Modified:	26 May 2026 09:26
URI:	https://orca.cardiff.ac.uk/id/eprint/187196

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