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

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 and Katalin Susztak ()
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Michael S. Balzer: University of Pennsylvania
Tomohito Doke: University of Pennsylvania
Ya-Wen Yang: University of Pennsylvania
Daniel L. Aldridge: University of Pennsylvania
Hailong Hu: University of Pennsylvania
Hung Mai: University of Pennsylvania
Dhanunjay Mukhi: University of Pennsylvania
Ziyuan Ma: University of Pennsylvania
Rojesh Shrestha: University of Pennsylvania
Matthew B. Palmer: University of Pennsylvania
Christopher A. Hunter: University of Pennsylvania
Katalin Susztak: University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31772-9

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