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Basement membrane turnover and circulating matrix biomarkers in kidney disease

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

DISEASE(S): Alport Syndrome

SUBMITTER: Anna Hoyle

LAB HEAD: Rachel Lennon

PROVIDER: PXD067091 | Pride | 2026-05-21

REPOSITORIES: Pride

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			Action	DRS
	20220118_LennonR_PrestonR_01.raw	Raw
	20220118_LennonR_PrestonR_02.raw	Raw
	20220118_LennonR_PrestonR_03.raw	Raw
	20220118_LennonR_PrestonR_04.raw	Raw
	20220118_LennonR_PrestonR_05.raw	Raw

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Project description:Background: The farnesoid X receptor (FXR) is a leading therapeutic target for MASH-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease. Methods: Leptin-deficient ob/ob mice were fed a MASH-inducing diet for 15 weeks prior to study start. After baseline liver biopsy and stratification, mice were allocated to INT-767 (10 mg/kg/day) or vehicle treatment for 8 weeks, either alongside ongoing MASH diet (progression) or following conversion to normal chow (reversal). Effects on extracellular matrix remodelling were analyzed histologically and by RNA-sequencing. Serum fibrosis biomarkers were measured longitudinally. Human liver samples were investigated using bulk and single-cell RNA-sequencing, histology, and cell culture assays. Results: INT-767 treatment was antifibrotic during MASH progression but not reversal, attenuating accumulation of type I collagen and basement membrane proteins (type IV collagen, laminin). Circulating levels of PRO-C4, a type IV collagen formation marker, were reduced by INT-767 treatment and correlated with fibrosis. Expression of basement membrane constituents also correlated with fibrosis severity and adverse clinical outcomes in human MASH. Single-cell RNA-sequencing analysis of mouse and human livers, and immunofluorescence staining colocalized FXR and basement membrane expression to myofibroblasts within the fibrotic niche. Treatment of culture-activated primary human hepatic stellate cells with INT-767 decreased expression of basement membrane components. Conclusion: These findings highlight the importance of basement membrane remodelling in MASH pathobiology and as a source of circulating biomarkers. Basement membrane deposition by activated hepatic stellate cells is abrogated by INT-767 treatment and measurement of basement membrane molecules should be included when determining the therapeutic efficacy of FXR agonists.

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Basement membrane turnover and circulating matrix biomarkers in kidney disease

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