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Kidney matrix dynamics across the life course

ABSTRACT: Chronic kidney disease (CKD) represents a major public health concern and accounts for massive morbidity, mortality, and financial resource. Advanced age is a major risk factor for progressive CKD and is associated with kidney fibrosis. Dysregulated protein turnover is a hallmark of ageing and leads to matrix accumulation and abnormal matrix remodelling. As there are no current effective therapies to prevent or reverse kidney fibrosis, there is an urgent need to understand mechanisms that drive aberrant kidney matrix remodelling that occurs during ageing. Using our established experimental workflow for global quantification of protein half-lives in the kidney, we pulse-labelled mice with 13C-Lysine and performed deep proteomic profiling across four time-points which spanned the physiological life course of mice. This approach enabled us to define the natural dynamics of protein turnover in the kidney and specifically examine the influence of development and ageing on kidney matrix dynamics. This study provides novel insights into the mechanisms of matrix deposition during kidney maturation and begins to unravel the influence of physiological ageing on abnormal kidney matrix remodelling and accumulation. We identify several age-related proteolytic cascades which become dysregulated with age. Targeting early fibrotic remodelling of kidney matrix could help ameliorate inflammation and serve as a powerful tool in combating subsequent progression of age-related CKD.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Anna Hoyle

LAB HEAD: Rachel Lennon

PROVIDER: PXD070694 | Pride | 2026-05-21

REPOSITORIES: Pride

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			Action	DRS
	20230203_LennonR_PrestonR_01.raw	Raw
	20230203_LennonR_PrestonR_02.raw	Raw
	20230203_LennonR_PrestonR_03.raw	Raw
	20230203_LennonR_PrestonR_04.raw	Raw
	20230203_LennonR_PrestonR_05.raw	Raw

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Project description:Chronic kidney disease (CKD) is characterised by kidney fibrosis and represents a major public health concern. Alport syndrome, a common monogenic cause of kidney failure caused by genetic variants in the type IV collagen genes COL4A3, COL4A4 or COL4A5, leads to abnormal basement membrane remodelling and kidney fibrosis. Understanding the dynamics and mechanisms of kidney matrix remodelling is crucial for directing emerging gene therapies and developing non-invasive biomarkers to detect and stage kidney fibrosis earlier, ultimately enabling risk stratification and timely intervention. To define the temporal and spatial dynamics of kidney matrix remodelling, we applied a multi-omics strategy in a Col4a5-/- mouse model of X-linked Alport syndrome, integrating stable isotope metabolic labelling, deep proteomic profiling, bulk RNA sequencing, super-resolution imaging, and bioinformatic prediction. Transcriptomic profiling identified enrichment of extracellular matrix degradation pathways and upregulation of matrix proteases. 13C-Lysine labelling coupled with mass spectrometry revealed altered abundance and accelerated turnover of basement membrane components in Alport kidneys. Super-resolution imaging confirmed spatial disorganisation of matrix proteins, supporting a loss of structural integrity. Using peptide location fingerprinting, we mapped damage modifications and predicted fragmentation in ~40 kidney matrix proteins, including collagens, laminins and nidogens. Targeted assays validated the presence of these predicted matrix fragments in serum from children with COL4A3–5 variants, demonstrating detectable alterations in circulating basement membrane peptides compared to healthy controls. These data define an uncoupling of matrix synthesis and degradation as a hallmark of Alport-associated kidney fibrosis. Our integrative approach establishes a framework for linking matrix proteolysis and basement membrane fragmentation with clinically accessible biomarkers of kidney matrix remodelling. The detection of circulating matrix fragments offers a promising non-invasive strategy to monitor basement membrane integrity and stage kidney fibrosis, with potential utility in both diagnosis and therapeutic response assessment in Alport syndrome and broader CKD contexts.

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Kidney matrix dynamics across the life course

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