Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease and is characterized by the formation and progressive expansion of kidney cysts. Most ADPKD cases arise from mutations in either the PKD1 or PKD2 gene but the precise downstream signaling pathways driving cyst growth are not well understood, and relatively few studies investigate human cystic kidney due to sample scarcity. In order to better understand the cell types and states driving human ADPKD progression, we analyzed eight ADPKD and five healthy human kidney samples, generating a single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. The integrated datasets identified 11 primary cell clusters including most epithelial cell types as well as large endothelial and fibroblast cell clusters. Proximal tubular cells from ADPKD kidneys expressed a failed repair transcriptomic signature characterized by profibrotic and proinflammatory transcripts. We identified the G protein-coupled receptor GPRC5A as specifically upregulated in cyst lining cells derived from collecting duct. The principal cell subpopulation enriched for GPRC5A expression also exhibited increased transcription factor binding motif availability for NF-{kappa}B, TEAD, CREB and retinoic acid receptor families and we identified and validated a distal enhancer regulating GPRC5A expression containing these transcription factor binding motifs. This study establishes the single cell transcriptomic and epigenomic landscape of ADPKD, revealing previously unrecognized cellular heterogeneity.