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A cross model spatial and single-cell atlas reveals the conserved involvement of osteopontin in polycystic kidney disease

ABSTRACT: 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). To elucidate the cellular and molecular consequences of these mutations, we constructed an integrated single-cell and spatial transcriptomics atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks. Single-cell and spatial transcriptomics revealed elevated Spp1 (osteopontin) expression enhanced signaling interactions with macrophages and fibroblasts in cystic niches. Whereas deletion of Spp1 increased cyst severity in the Ift88 model, it reduced PKD severity in the orthologous Pkd1RC/RC model, concurrent with model-specific differences in Spp1 cell type expression and communication partners. We also found increased SPP1 expression and signaling in single-cell RNA sequencing data from autosomal dominant PKD (ADPKD) patients, highlighting cross-species conservation. Together, our integrated atlas identified conserved intercellular signaling networks within cystic niches, including SPP1, offering insights into PKD pathogenesis and potential therapeutic targets.Conclusion: Collectively, our data indicate that tVNS improves HFpEF by reducing Spp1 expressing CCR2+ CRM and inducing expression of pro-reparative Igf1 in TLF+/MHC2+ CRM. These effects are mediated through cholinergic signaling, highlighting a neuroimmune pathway in HFpEF.

ORGANISM(S): Mus musculus

PROVIDER: GSE298379 | GEO | 2026/06/15

REPOSITORIES: GEO

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Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.

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A cross model spatial and single-cell atlas reveals the conserved involvement of osteopontin in polycystic kidney disease

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