Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Nature communications - 13(2022), 1 vom: 11. Juli, Seite 4018 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Balzer, Michael S [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 14.07.2022 Date Revised 17.08.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-022-31772-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM343417421 |
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| 245 | 1 | 0 | |a Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Doke, Tomohito |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Ya-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Aldridge, Daniel L |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Hailong |e verfasserin |4 aut | |
| 700 | 1 | |a Mai, Hung |e verfasserin |4 aut | |
| 700 | 1 | |a Mukhi, Dhanunjay |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Ziyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Shrestha, Rojesh |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Matthew B |e verfasserin |4 aut | |
| 700 | 1 | |a Hunter, Christopher A |e verfasserin |4 aut | |
| 700 | 1 | |a Susztak, Katalin |e verfasserin |4 aut | |
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