What’s so special about the female kidney? Using single nuclear RNA sequencing to understand proximal tubular cell heterogeneity

Smith, Tanya 2026. What’s so special about the female kidney? Using single nuclear RNA sequencing to understand proximal tubular cell heterogeneity. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

AKI carries substantial morbidity and mortality. The proximal tubule is the primary site of injury in renal IRI, and the balance between adaptive and failed repair determines progression to CKD. Although sex and age influence outcomes, the underlying mechanisms remain unclear. This thesis applies single-nucleus multiomic profiling to define sex- and age-specific proximal tubular state transitions after injury. The first results chapter demonstrates greater acute injury and persistent profibrotic signalling in male compared with female mice in a bilateral IRI model. The second chapter presents an integrated snRNA-seq and snATAC-seq atlas (30, 396; n = 16) from adult and elderly male and female kidneys at baseline and after injury. Following IRI, proximal tubular cells diverged into acute injury, repair, and failed repair states. Failed repair clusters retained injury markers, suppressed transport programmes, and showed coordinated epigenetic activation of inflammatory and extracellular matrix pathways. The final chapter identifies metabolic reprogramming and transcriptional instability within maladaptive states. Male and aged kidneys exhibited suppression of oxidative phosphorylation and fatty acid β-oxidation, whereas female and adult kidneys showed relative metabolic preservation. InferCNV analysis revealed reproducible chromosomal expression shifts within failed repair clusters. Collectively, this work defines sex- and age-specific proximal tubular phenotypes and identifies metabolic and regulatory pathways that may underlie differential injury responses.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	13 October 2026
Last Modified:	19 Oct 2026 15:42
URI:	https://orca.cardiff.ac.uk/id/eprint/190122

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