Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair

Elife. 2021 Jul 19:10:e68603. doi: 10.7554/eLife.68603.


Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.

Keywords: cell biology; ferroptosis; kidney injury; mouse; regenerative medicine; repair; single-cell RNA sequencing; stem cells.

Publication types

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

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / therapy
  • Animals
  • Cell Death
  • Epithelial Cells / metabolism*
  • Ferroptosis / genetics
  • Fibrosis / genetics
  • Gene Expression
  • Inflammation / genetics
  • Iron / metabolism
  • Kidney / injuries*
  • Kidney / metabolism*
  • Kidney / pathology
  • Lipid Peroxidation
  • Male
  • Mice
  • Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
  • Regenerative Medicine


  • Iron
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • glutathione peroxidase 4, mouse

Associated data

  • GEO/GSE161201
  • GEO/GSE94333
  • GEO/GSE131882
  • GEO/GSE145927