Circadian dynamics and matrix protein turnover in the kidney glomerulus

Abstract

Glomerular disease represents the leading cause of chronic kidney disease (CKD) and is characterised by ultrastructural alteration in the glomerular basement membrane (GBM), a highly specialised matrix. The molecular mechanisms underlying the spatiotemporal regulation of GBM homeostasis, and the pathogenesis of GBM abnormalities remains largely unsolved. Understanding drivers of aberrant kidney matrix deposition is key to identifying strategies to prevent kidney fibrosis and prolong organ survival. In this thesis, I aimed to uncover the molecular components of the glomerular circadian clock and investigate the dynamics of matrix protein turnover in the kidney during development, ageing and disease. With clock gene reporter mice, I demonstrated the presence of glomerular clocks. Using circadian time-series transcriptomic profiling, I report the first circadian glomerular transcriptome, revealing a subset of rhythmic extracellular matrix genes required for basement membrane assembly and turnover. I found podocyte-intrinsic autonomous clocks which respond to glucocorticoid treatment and temporally control key genes involved in glomerular function and disease. The circadian regulation of matrix homeostasis and the discovery of a glucocorticoid responsive functional connection between kidney filtration and the circadian system provides new molecular mechanisms and potential therapeutic targets for the treatment of glomerular disease. Using 13C-Lysine labelled mice and deep proteomic profiling, I proceeded to define kidney matrix protein turnover at the molecular level in disease and across the physiological lifecourse. I demonstrated the dynamic nature of the kidney matrisome and I present potential mechanisms of aberrant matrix remodelling in the face of insult, thereby progressing understanding of the pathogenesis of CKD. Finally, I identified several matrix components which could be exploited as biomarkers for kidney fibrosis, or serve as potential therapeutic targets, to ameliorate or prevent progression of declining kidney function. Overall, this thesis provides new insight into the temporal regulation of the kidney matrix and the pathogenesis of dysregulated matrix dynamics in CKD, thus contributing important knowledge to the fields of circadian research and matrix biology.

Date of Award	1 May 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Qing-Jun Meng (Supervisor) & Rachel Lennon (Supervisor)