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Updated: Jun 10, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Multiomics profiling of mouse polycystic kidney disease progression at a single-cell resolution
Yoshiharu Muto1, Yasuhiro Yoshimura2, Haojia Wu2
1Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Abstract:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. 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 catalog 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 autosomal dominant polycystic kidney disease (ADPKD) using a mouse model. It reveals cell-specific responses to Pkd1 deletion, aiding understanding of kidney disease progression.
Area of Science:
- Genomics
- Molecular Biology
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disorder leading to kidney failure.
- Understanding ADPKD pathogenesis requires detailed analysis of cellular changes during disease progression.
Purpose of the Study:
- To create a comprehensive single-nucleus multimodal atlas of a mouse model of ADPKD.
- To characterize cell-type-specific molecular alterations during PKD progression at single-cell resolution.
Main Methods:
- Generated a single-nucleus multiomic atlas (transcriptomic and epigenetic) from an orthologous mouse PKD model.
- Analyzed data from early, mid, and late disease timepoints, encompassing 125,434 nuclei.
- Identified differentially expressed genes and activated epigenetic regions in various cell types.
Main Results:
- Cataloged cell-type-specific responses to Pkd1 deletion during PKD progression.
- Identified heterogeneous, atypical collecting duct and proximal tubular cells forming cyst epithelia.
- Found conserved transcriptional regulation of GPRC5A in mouse and human PKD cystic epithelia.
Conclusions:
- The single-nucleus multiomic atlas provides a foundational resource for studying ADPKD.
- Reveals earliest molecular changes and cell-type-specific responses in a PKD mouse model.
- Highlights conserved gene regulatory pathways in PKD cyst formation.
