PT  - JOURNAL ARTICLE
AU  - Shintaro Ide
AU  - Yoshihiko Kobayashi
AU  - Kana Ide
AU  - Sarah A. Strausser
AU  - Savannah Herbek
AU  - Lori L. O’Brien
AU  - Steven D. Crowley
AU  - Laura Barisoni
AU  - Aleksandra Tata
AU  - Purushothama Rao Tata
AU  - Tomokazu Souma
TI  - Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair
AID  - 10.1101/2021.03.23.436661
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.23.436661
4099  - http://biorxiv.org/content/early/2021/03/23/2021.03.23.436661.short
4100  - http://biorxiv.org/content/early/2021/03/23/2021.03.23.436661.full
AB  - 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, they accumulate and contribute to persistent inflammation after severe injury. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making them 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.Competing Interest StatementThe authors have declared no competing interest.