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Abstract: TH-OR012

A Comprehensive Single Nucleus RNA-Sequencing Atlas of Mouse and Human AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Kirita, Yuhei, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, United States
  • Wu, Haojia, Washington University School of Medicine in St. Louis, Saint Louis, Missouri, United States
  • Humphreys, Benjamin D., Washington University School of Medicine in St. Louis, Saint Louis, Missouri, United States

After acute kidney injury (AKI), many patients make an apparently full recovery (“complete repair”) whereas others transition to chronic kidney disease (CKD, “failed repair”). To better define the cellular and molecular mechanisms of AKI and the AKI to CKD transition, we performed comprehensive single nucleus RNA-seq (snRNA-seq) on both mouse and human AKI.


We generated 122,828 single-nucleus transcriptomes from mouse kidney after IRI: 4 hours, 12 hours, 2 days, 14 days, 6 weeks and sham (n = 3 for each), and 37,636 nuclei from a healthy and AKI adult human kidney using the 10X platform and performed a comprehensive informatic analysis and gene expression validation.


Mouse had on average 1317 and human 2007 unique genes/nucleus. We identified over 30 cell types including rare ones (juxtaglomerulus, macula densa) in both mouse and human datasets. We define transcriptional states that distinguish proximal tubule destined for successful vs. failed repair. Using receptor-ligand analysis, we identify and define profibrotic and pro-inflammatory signals secreted by failed repair epithelia to fibroblasts, endothelial cells and leukocytes, driving the AKI to CKD transition. We show that a scattered cell population in healthy kidney exists that recapitulates the epithelial repair signature and that likely represents the cell type that prior reports characterized as a fixed stem cell population. We define 9 stromal subtypes including four novel fibroblast and 3 novel pericyte cell types and find that a subset transiently upregulate aSMA after injury. These results were validated in the human AKI snRNA-seq dataset.


The first comprehensive snRNA-seq atlas of mouse and human AKI kidney revealed four novel insights: (1) injury-repair cycles occur in situ in single epithelial cells in healthy kidney, (2) a population of pro-fibrotic proximal tubule cells drives failed repair in a non cell-autonomous manner, (3) novel stromal subtypes are identified including a population with reversible expression of aSMA, suggesting plasticity amongst myofibroblast progenitors and (5) a receptor-ligand analysis between all major kidney cell types during injury and repair reveals dynamic intercellular communication patterns.


  • Private Foundation Support