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 and Benjamin D. Humphreys ()
Additional contact information
Yoshiharu Muto: Washington University in St. Louis
Eryn E. Dixon: Washington University in St. Louis
Yasuhiro Yoshimura: Washington University in St. Louis
Haojia Wu: Washington University in St. Louis
Kohei Omachi: Washington University in St. Louis
Nicolas Ledru: Washington University in St. Louis
Parker C. Wilson: Washington University in St. Louis
Andrew J. King: Chinook Therapeutics, Inc.
N. Eric Olson: Chinook Therapeutics, Inc.
Marvin G. Gunawan: Chinook Therapeutics, Inc.
Jay J. Kuo: Chinook Therapeutics, Inc.
Jennifer H. Cox: Chinook Therapeutics, Inc.
Jeffrey H. Miner: Washington University in St. Louis
Stephen L. Seliger: University of Maryland School of Medicine
Owen M. Woodward: University of Maryland School of Medicine
Paul A. Welling: Johns Hopkins School of Medicine
Terry J. Watnick: University of Maryland School of Medicine
Benjamin D. Humphreys: Washington University in St. Louis

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34255-z

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