@article{b43e907024704b3fb664c65909d05f09,
title = "Comprehensive single-cell transcriptional profiling defines shared and unique epithelial injury responses during kidney fibrosis",
abstract = "The underlying cellular events driving kidney fibrogenesis and metabolic dysfunction are incompletely understood. Here, we employed single-cell combinatorial indexing RNA sequencing to analyze 24 mouse kidneys from two fibrosis models. We profiled 309,666 cells in one experiment, representing 50 cell types/states encompassing epithelial, endothelial, immune, and stromal populations. Single-cell analysis identified diverse injury states of the proximal tubule, including two distinct early-phase populations with dysregulated lipid and amino acid metabolism, respectively. Lipid metabolism was defective in the chronic phase but was transiently activated in the very early stages of ischemia-induced injury, where we discovered increased lipid deposition and increased fatty acid β-oxidation. Perilipin 2 was identified as a surface marker of intracellular lipid droplets, and its knockdown in vitro disrupted cell energy state maintenance during lipid accumulation. Surveying epithelial cells across nephron segments identified shared and unique injury responses. Stromal cells exhibited high heterogeneity and contributed to fibrogenesis by epithelial-stromal crosstalk.",
keywords = "PLIN2, acute kidney injury, cell differentiation, chronic kidney disease, fibrosis, kidney, lipid droplet, lipid metabolism, single-cell combinatorial indexing, tissue regeneration",
author = "Haikuo Li and Dixon, {Eryn E.} and Haojia Wu and Humphreys, {Benjamin D.}",
note = "Funding Information: B.D.H. is a consultant for Janssen Research & Development, LLC, Pfizer, and Chinook Therapeutics and holds equity in Chinook Therapeutics and grant funding from Chinook Therapeutics, Janssen Research & Development, LLC, and Pfizer; all interests are unrelated to the current work. Funding Information: These experiments were funded by NIH grants DK103740 and UC2DK126024 to B.D.H. The authors acknowledge the Washington University Diabetes Research Center for providing training for Seahorse Analyzer applications. The authors also acknowledge the Washington University Genome Technology Access Center and Center for Genome Sciences & Systems Biology for sequencing support. H.L. and B.D.H. conceived, coordinated, and designed the study. H.L. performed experiments with contributions from E.E.D. and H.W.; H.L. and B.D.H. analyzed data. H.L. and B.D.H. wrote the manuscript. All authors read and approved the final manuscript. B.D.H. is a consultant for Janssen Research & Development, LLC, Pfizer, and Chinook Therapeutics and holds equity in Chinook Therapeutics and grant funding from Chinook Therapeutics, Janssen Research & Development, LLC, and Pfizer; all interests are unrelated to the current work. We support inclusive, diverse, and equitable conduct of research. Funding Information: These experiments were funded by NIH grants DK103740 and UC2DK126024 to B.D.H. The authors acknowledge the Washington University Diabetes Research Center for providing training for Seahorse Analyzer applications. The authors also acknowledge the Washington University Genome Technology Access Center and Center for Genome Sciences & Systems Biology for sequencing support. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = dec,
day = "6",
doi = "10.1016/j.cmet.2022.09.026",
language = "English",
volume = "34",
pages = "1977--1998.e9",
journal = "Cell Metabolism",
issn = "1550-4131",
number = "12",
}