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Spotlight on Kidney Fibrosis

Kidney fibrosis is the hallmark of chronic kidney disease (CKD) progression; however, no current antifibrotic therapies exist due to the intricate cellular mechanisms involved in fibrosis and the origin of scar-forming cells in human kidney fibrosis is still debated.

CKD is an incurable condition that requires dialysis and ultimately kidney transplant. In the UK, the waiting time on average for a deceased donor kidney transplant is 2.5 to 3 years due to the high demand, with the possibility that many patients could die prematurely from lack of access to renal replacement. Therefore, CKD is a at present an unmet clinical need that requires comprehensive study to prevent and treat it.

A recent study by Rafael Kramann, Christoph Kuppe, Mahmoud Ibrahim and colleagues, profiled cells from the proximal and non-proximal tubules of CKD patients to map the entire human kidney. The researchers identified the majority of COL1A1 expressing cells as PDGFRβ+ and provided an unprecedented insight into fibroblast-to-myofibroblast and pericyte-to-myofibroblast differentiation trajectories.

The authors established an extracellular matrix (ECM) expression score including collagens, proteoglycans, and glycoproteins, which are the major constituents of the ECM. The ECM scores demonstrated that mesenchymal cells, such as myofibroblasts, are the main contributors to human kidney fibrosis.

Diffusion mapping of high ECM-expressing mesenchymal cells demonstrated that myofibroblasts arise from both pericytes and fibroblasts.

Dual positive PDGFRα+ and PDGFRβ+ fibroblasts were found in scar tissue in mice and humans.

Multiplexed RNA in situ hybridization (ISH) showed Ccl19+/Ccl21+ myofibroblasts around the glomeruli in early fibrosis, which were further increased in late-stage fibrosis.

Genetic fate-tracing experiments in kidneys from Pdgfrb-creER-tdTomato mice, ISH and immunostaining confirmed that almost all myofibroblasts are derived from the PDGFRβ lineage.

Overexpression of NKD2 in human a PDGFRβ+ cell line increased COL1A1, FN1 and ACTA2 in response to 24h TGFβ treatment.

IL-1β induced fibrosis in pluripotent stem (iPS) cell-derived kidney organoids, whilst short interfering RNA-mediated knockdown of NKD2 inhibited, indicating that NKD2 is required for collagen expression.

Consequently, the authors identified NKD2 as a myofibroblast-specific target in human kidney fibrosis and suggested NKD2 as a potential therapeutic target.

By using single-cell RNA sequencing, this work generated a compelling CKD map to further understand disease drivers and eventually develop drug candidates for clinical research i.e. NKD2 inhibitors.

Reference

Kuppe, C., Ibrahim, M.M., Kranz, J. et al. Decoding myofibroblast origins in human kidney fibrosis. Nature 589, 281-286 (2021)
doi: 10.1038/s41586-020-2941-1

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