A cross model single-cell atlas reveals conserved involvement of osteopontin in polycystic kidney disease
Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as PKD1 and PKD2 , expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell RNA sequencing atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Across models, single cell RNA sequencing (scRNAseq) data revealed increased Spp1 (osteopontin) expression and signaling from PKD-enriched clusters. Global deletion of Spp1 in Pkd1 RC/RC mice resulted in a modest reduction in cyst severity and improved kidney function. From these studies, we created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.
Authors
- Jason R. Stubbs (ORCID: https://orcid.org/0000-0003-4580-5745)
- Chelsea N. Zimmerman
- Qin Ma (ORCID: https://orcid.org/0000-0002-3264-8392)
- Hua Zhong (ORCID: https://orcid.org/0000-0003-1962-2603)
- Alex Yashchenko (ORCID: https://orcid.org/0000-0003-2558-7752)
- Katharina Hopp (ORCID: https://orcid.org/0000-0002-2420-2358)
- Jenny Gipson
- Benjamin D. Cowley (ORCID: https://orcid.org/0000-0003-4761-6075)
- Bradley K. Yoder (ORCID: https://orcid.org/0000-0002-0247-1944)
- Mary C.M. Weiser‐Evans (ORCID: https://orcid.org/0000-0002-6239-2412)
- Anjun Ma (ORCID: https://orcid.org/0000-0001-6269-398X)
- David A. Long (ORCID: https://orcid.org/0000-0001-6580-3435)
- Zhang Li (ORCID: https://orcid.org/0000-0002-3796-0369)
- Sizhao Lu (ORCID: https://orcid.org/0000-0002-9892-8784)
- Fariha Nusrat (ORCID: https://orcid.org/0000-0002-8624-721X)
- Kurt A. Zimmerman (ORCID: https://orcid.org/0000-0003-1798-8046)
- Daniyal J. Jafree (ORCID: https://orcid.org/0000-0001-8235-0394)
- Xiaogang Li (ORCID: https://orcid.org/0000-0001-8135-342X)
- Audrey M. Cordova (ORCID: https://orcid.org/0009-0004-7444-7419)
- Xiaoyan Li
- Vicki Do
- Dr Bibi Maryam
- Sarah J. Miller (ORCID: https://orcid.org/0000-0003-4888-5306)
- Morgan E. Yashchenko (ORCID: https://orcid.org/0009-0002-6582-8645)
- Weidong Wu
- Yohan Park
- Maya E. Hignite
- Christa I. DeVette
Institutions
- Boston Children's Hospital (US)
- University of Alabama at Birmingham (US)
- University of Kansas Medical Center (US)
- Mayo Clinic in Florida (US)
- Boston Children's Museum (US)
- University College London (GB)
- University of Oklahoma Health Sciences Center (US)
- University of Colorado Anschutz Medical Campus (US)
- The Ohio State University (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2026-07-28
- DOI
- https://doi.org/10.1172/jci.insight.207157
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00