Single-cell sequencing dissects the transcriptional identity of activated fibroblasts and identifies novel persistent distal tubular injury patterns in kidney fibrosis.

Autor: Rudman-Melnick V; Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA., Adam M; Division Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Stowers K; Division Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Potter A; Division Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Ma Q; Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA., Chokshi SM; Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA., Vanhoutte D; Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA., Valiente-Alandi I; Cytokinetics, San Francisco, CA, USA., Lindquist DM; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.; Department of Radiology, University of Cincinnati, Cincinnati, OH, USA.; Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Nieman ML; Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, USA., Kofron JM; Division Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA., Chung E; Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL, USA., Park JS; Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Feinberg Cardiovascular and Renal Research Institute, Northwestern University, Chicago, IL, USA., Potter SS; Division Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA., Devarajan P; Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA. prasad.devarajan@cchmc.org.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. prasad.devarajan@cchmc.org.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jan 03; Vol. 14 (1), pp. 439. Date of Electronic Publication: 2024 Jan 03.
DOI: 10.1038/s41598-023-50195-0
Abstrakt: Examining kidney fibrosis is crucial for mechanistic understanding and developing targeted strategies against chronic kidney disease (CKD). Persistent fibroblast activation and tubular epithelial cell (TEC) injury are key CKD contributors. However, cellular and transcriptional landscapes of CKD and specific activated kidney fibroblast clusters remain elusive. Here, we analyzed single cell transcriptomic profiles of two clinically relevant kidney fibrosis models which induced robust kidney parenchymal remodeling. We dissected the molecular and cellular landscapes of kidney stroma and newly identified three distinctive fibroblast clusters with "secretory", "contractile" and "vascular" transcriptional enrichments. Also, both injuries generated failed repair TECs (frTECs) characterized by decline of mature epithelial markers and elevation of stromal and injury markers. Notably, frTECs shared transcriptional identity with distal nephron segments of the embryonic kidney. Moreover, we identified that both models exhibited robust and previously unrecognized distal spatial pattern of TEC injury, outlined by persistent elevation of renal TEC injury markers including Krt8 and Vcam1, while the surviving proximal tubules (PTs) showed restored transcriptional signature. We also found that long-term kidney injuries activated a prominent nephrogenic signature, including Sox4 and Hox gene elevation, which prevailed in the distal tubular segments. Our findings might advance understanding of and targeted intervention in fibrotic kidney disease.
(© 2024. The Author(s).)
Databáze: MEDLINE
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