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Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration

Author

Listed:
  • Michael S. Balzer

    (University of Pennsylvania
    University of Pennsylvania)

  • Tomohito Doke

    (University of Pennsylvania
    University of Pennsylvania)

  • Ya-Wen Yang

    (University of Pennsylvania
    University of Pennsylvania)

  • Daniel L. Aldridge

    (University of Pennsylvania)

  • Hailong Hu

    (University of Pennsylvania
    University of Pennsylvania)

  • Hung Mai

    (University of Pennsylvania
    University of Pennsylvania)

  • Dhanunjay Mukhi

    (University of Pennsylvania
    University of Pennsylvania)

  • Ziyuan Ma

    (University of Pennsylvania
    University of Pennsylvania)

  • Rojesh Shrestha

    (University of Pennsylvania
    University of Pennsylvania)

  • Matthew B. Palmer

    (University of Pennsylvania)

  • Christopher A. Hunter

    (University of Pennsylvania)

  • Katalin Susztak

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic repair are poorly understood. We developed a model of adaptive and fibrotic kidney regeneration by titrating ischemic injury dose. We performed detailed biochemical and histological analysis and profiled transcriptomic changes at bulk and single-cell level (> 110,000 cells) over time. Our analysis highlights kidney proximal tubule cells as key susceptible cells to injury. Adaptive proximal tubule repair correlated with fatty acid oxidation and oxidative phosphorylation. We identify a specific maladaptive/profibrotic proximal tubule cluster after long ischemia, which expresses proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors. Druggability analysis highlights pyroptosis/ferroptosis as vulnerable pathways in these profibrotic cells. Pharmacological targeting of pyroptosis/ferroptosis in vivo pushed cells towards adaptive repair and ameliorates fibrosis. In summary, our single-cell analysis defines key differences in adaptive and fibrotic repair and identifies druggable pathways for pharmacological intervention to prevent kidney fibrosis.

Suggested Citation

  • Michael S. Balzer & Tomohito Doke & Ya-Wen Yang & Daniel L. Aldridge & Hailong Hu & Hung Mai & Dhanunjay Mukhi & Ziyuan Ma & Rojesh Shrestha & Matthew B. Palmer & Christopher A. Hunter & Katalin Suszt, 2022. "Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31772-9
    DOI: 10.1038/s41467-022-31772-9
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    References listed on IDEAS

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    1. Haojia Wu & Eryn E. Dixon & Qiao Xuanyuan & Juanru Guo & Yasuhiro Yoshimura & Chitnis Debashish & Anezka Niesnerova & Hao Xu & Morgane Rouault & Benjamin D. Humphreys, 2024. "High resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Lingzhi Li & Ting Xiang & Jingjing Guo & Fan Guo & Yiting Wu & Han Feng & Jing Liu & Sibei Tao & Ping Fu & Liang Ma, 2024. "Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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