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

eLife

Lori L O'Brien¹  Yoshihiko Kobayashi²  Aleksandra Tata²  Purushothama Rao Tata³  Shintaro Ide⁴  Steven D Crowley⁴  Savannah Herbek⁴  Koki Abe⁴  Sarah A Strausser⁴  Kana Ide⁴  Laura Barisoni⁵  Tomokazu Souma⁶ 

[1] Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States;Department of Cell Biology, Duke University School of Medicine, Durham, United States;Department of Cell Biology, Duke University School of Medicine, Durham, United States;Regeneration Next, Duke University, Durham, United States;Duke Cancer Institute, Duke University School of Medicine, Durham, United States;Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States;Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States;Department of Pathology, Duke University School of Medicine, Durham, United States;Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States;Regeneration Next, Duke University, Durham, United States;

关键词: single-cell RNA sequencing;    ferroptosis;    kidney injury;    repair;    Mouse;   

DOI  :  10.7554/eLife.68603

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY