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; Katalin Susztak

doi:10.1038/s41467-022-31772-9

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

Nat Commun. 2022 Jul 11;13(1):4018. doi: 10.1038/s41467-022-31772-9.

Authors

Michael S Balzer^{1

2}, Tomohito Doke^{1

2}, Ya-Wen Yang^{1

2}, Daniel L Aldridge³, Hailong Hu^{1

2}, Hung Mai^{1

2}, Dhanunjay Mukhi^{1

2}, Ziyuan Ma^{1

2}, Rojesh Shrestha^{1

2}, Matthew B Palmer⁴, Christopher A Hunter³, Katalin Susztak^{5

6

7}

Affiliations

¹ Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
² Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
³ Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁴ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁵ Renal, Electrolyte, and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. ksusztak@pennmedicine.upenn.edu.
⁶ Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. ksusztak@pennmedicine.upenn.edu.
⁷ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. ksusztak@pennmedicine.upenn.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury* / drug therapy
Acute Kidney Injury* / genetics
Acute Kidney Injury* / metabolism
Fibrosis
Humans
Kidney* / metabolism
Regeneration
Single-Cell Analysis