Comprehensive single-cell transcriptional profiling defines shared and unique epithelial injury responses during kidney fibrosis.

1. Cell Metab. 2022 Dec 6;34(12):1977-1998.e9. doi: 10.1016/j.cmet.2022.09.026. Epub 2022 Oct 19. Comprehensive single-cell transcriptional profiling defines shared and unique epithelial injury responses during kidney fibrosis. Li H(1), Dixon EE(1), Wu H(1), Humphreys BD(2). Author information: (1)Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA. (2)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. Electronic address: humphreysbd@wustl.edu. Comment in Nat Rev Nephrol. 2023 Jan;19(1):3. doi: 10.1038/s41581-022-00657-x. Kidney Int. 2023 Jul;104(1):19-21. doi: 10.1016/j.kint.2023.02.005. 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. Copyright © 2022 Elsevier Inc. All rights reserved. DOI: 10.1016/j.cmet.2022.09.026 PMCID: PMC9742301 PMID: 36265491 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests 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.