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Updated: Dec 1, 2025
Unilateral Ureteral Obstruction Model for Investigating Kidney Interstitial Fibrosis
Published on: April 25, 2025
Decoding myofibroblast origins in human kidney fibrosis
Christoph Kuppe1,2, Mahmoud M Ibrahim1,2,3, Jennifer Kranz2,4,5
1Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
Abstract:
Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1-3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis.
Insights
Researchers identified the cellular origins of kidney fibrosis, revealing specific pericyte and fibroblast subpopulations as key contributors. This discovery paves the way for developing novel antifibrotic therapies targeting myofibroblasts.
Area of Science:
- Nephrology
- Cell Biology
- Genomics
Background:
- Kidney fibrosis is a primary driver of chronic kidney disease (CKD) progression.
- Current therapeutic options for kidney fibrosis are limited, highlighting an unmet clinical need.
- The cellular sources and regulation of scar-forming cells in human kidney fibrosis are not well understood.
Purpose of the Study:
- To comprehensively map cellular populations in healthy and fibrotic human kidneys.
- To identify the specific cell types responsible for myofibroblast differentiation during kidney fibrosis.
- To discover potential therapeutic targets for antifibrotic treatments.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) of human kidney cells.
- Genetic fate-tracing and time-course scRNA-seq in mouse models.
- Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) in mice.
- Spatial transcriptomics of human fibrotic kidney tissue.
Main Results:
- High-resolution mapping of matrix-producing cells in the human kidney.
- Identification of distinct pericyte and fibroblast subpopulations as major sources of myofibroblasts.
- Elucidation of the cellular origins and differentiation pathways of myofibroblasts.
- Discovery of NKD2 as a myofibroblast-specific target.
Conclusions:
- Pericytes and fibroblasts are key cellular precursors of myofibroblasts in human kidney fibrosis.
- Understanding these cellular dynamics provides insights into fibrosis mechanisms.
- NKD2 represents a promising therapeutic target for treating kidney fibrosis.
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