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

Yoshiharu Muto, Eryn E. Dixon, Yasuhiro Yoshimura, Haojia Wu, Kohei Omachi, Nicolas Ledru, Parker C. Wilson, Andrew J. King, N. Eric Olson, Marvin G. Gunawan, Jay J. Kuo, Jennifer H. Cox, Jeffrey H. Miner, Stephen L. Seliger, Owen M. Woodward, Paul A. Welling, Terry J. Watnick, Benjamin D. Humphreys

Research output: Contribution to journalArticlepeer-review

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches.

Original languageEnglish (US)
Article number6497
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology

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