Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration.
Michael S BalzerTomohito DokeYa-Wen YangDaniel L AldridgeHailong HuHung MaiDhanunjay MukhiZiyuan MaRojesh ShresthaMatthew B PalmerChristopher A HunterKatalin SusztákPublished in: Nature communications (2022)
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.
Keyphrases
- single cell
- induced apoptosis
- cell cycle arrest
- cell death
- rna seq
- stem cells
- systemic sclerosis
- idiopathic pulmonary fibrosis
- randomized controlled trial
- endoplasmic reticulum stress
- high throughput
- bone marrow
- mesenchymal stem cells
- signaling pathway
- genome wide
- nitric oxide
- cell proliferation
- dna methylation
- subarachnoid hemorrhage
- pulmonary fibrosis
- cerebral ischemia