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

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Tytuł:: Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis.
Autorzy:: Muto Y; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Dixon EE; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Yoshimura Y; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Wu H; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Omachi K; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Ledru N; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Wilson PC; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.
King AJ; Chinook Therapeutics, Inc., Seattle, WA, USA.
Eric Olson N; Chinook Therapeutics, Inc., Seattle, WA, USA.
Gunawan MG; Chinook Therapeutics, Inc., Vancouver, BC, Canada.
Kuo JJ; Chinook Therapeutics, Inc., Vancouver, BC, Canada.
Cox JH; Chinook Therapeutics, Inc., Vancouver, BC, Canada.
Miner JH; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
Seliger SL; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Woodward OM; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Welling PA; Johns Hopkins School of Medicine, Baltimore, MD, USA.
Watnick TJ; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Humphreys BD; Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA. .; Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, USA. .
Źródło:: Nature communications [Nat Commun] 2022 Oct 30; Vol. 13 (1), pp. 6497. Date of Electronic Publication: 2022 Oct 30.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Polycystic Kidney, Autosomal Dominant*/genetics
Polycystic Kidney, Autosomal Dominant*/metabolism
Cysts*/metabolism
Humans ; Single-Cell Analysis ; Kidney/metabolism ; Kidney Tubules/metabolism ; Epithelial Cells/metabolism ; Receptors, G-Protein-Coupled/metabolism
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Grant Information:: K08 DK126847 United States DK NIDDK NIH HHS; P30 DK090868 United States DK NIDDK NIH HHS
Substance Nomenclature:: 0 (GPRC5A protein, human)
0 (Receptors, G-Protein-Coupled)
Entry Date(s):: Date Created: 20221031 Date Completed: 20221101 Latest Revision: 20231110
Update Code:: 20240105
PubMed Central ID:: PMC9618568
DOI:: 10.1038/s41467-022-34255-z
PMID:: 36310237
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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.
(© 2022. The Author(s).)

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