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Updated: Jun 24, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution
Yoshiharu Muto1, Yasuhiro Yoshimura1, Haojia Wu1
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to end-stage kidney disease. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single nucleus multimodal atlas of an orthologous mouse PKD model at early, mid and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalogue differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.
Insights
This study maps the cellular and molecular changes in a mouse model of Autosomal Dominant Polycystic Kidney Disease (ADPKD). The findings reveal cell-type-specific responses to Pkd1 deletion, offering insights into disease mechanisms.
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary kidney disorder.
- ADPKD leads to significant morbidity and end-stage kidney disease.
- Disease progression involves complex cellular changes, hindering mechanistic understanding and therapy development.
Purpose of the Study:
- To create a single-nucleus multimodal atlas of a mouse PKD model.
- To characterize cell-type-specific molecular alterations during PKD progression.
- To identify shared gene regulatory pathways in PKD epithelia.
Main Methods:
- Generation of a single nucleus multimodal atlas from an orthologous mouse PKD model.
- Analysis of 125,434 single-nucleus transcriptomic and epigenetic multiomes.
- Cataloguing differentially expressed genes and epigenetic regions across disease timepoints.
Main Results:
- Detailed characterization of cell-type-specific responses to Pkd1 deletion.
- Identification of heterogeneous, atypical collecting duct and proximal tubular cells in cysts.
- Discovery of conserved transcriptional regulation of GPRC5A in mouse and human PKD epithelia.
Conclusions:
- The study provides a single-cell resolution molecular atlas of PKD progression in a mouse model.
- Findings offer a foundation for understanding early molecular deregulation in PKD.
- Identified conserved pathways suggest potential therapeutic targets.
