Ferroptotic Stress Promotes the Accumulation of Pro-inflammatory Proximal Tubular Cells in Maladaptive Renal Repair

Overview

Journal Elife

Specialty Biology

Date 2021 Jul 19

PMID 34279220

Citations 57

Authors

Shintaro Ide

Yoshihiko Kobayashi

Kana Ide

Sarah A Strausser

Koki Abe

Savannah Herbek

Lori L OBrien

Steven D Crowley

Laura Barisoni

Aleksandra Tata

Purushothama Rao Tata

Tomokazu Souma

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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References

Hauser I, Riess R, Hausknecht B, Thuringer H, Sterzel R . Expression of cell adhesion molecules in primary renal disease and renal allograft rejection. Nephrol Dial Transplant. 1997; 12(6):1122-31. DOI: 10.1093/ndt/12.6.1122. View

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

Macosko E, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M . Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015; 161(5):1202-1214. PMC: 4481139. DOI: 10.1016/j.cell.2015.05.002. View

Browaeys R, Saelens W, Saeys Y . NicheNet: modeling intercellular communication by linking ligands to target genes. Nat Methods. 2019; 17(2):159-162. DOI: 10.1038/s41592-019-0667-5. View

Combes A, Phipson B, Lawlor K, Dorison A, Patrick R, Zappia L . Single cell analysis of the developing mouse kidney provides deeper insight into marker gene expression and ligand-receptor crosstalk. Development. 2019; 146(12). DOI: 10.1242/dev.178673. View

Tiwari N, Tiwari V, Waldmeier L, Balwierz P, Arnold P, Pachkov M . Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming. Cancer Cell. 2013; 23(6):768-83. DOI: 10.1016/j.ccr.2013.04.020. View

Ransick A, Lindstrom N, Liu J, Zhu Q, Guo J, Alvarado G . Single-Cell Profiling Reveals Sex, Lineage, and Regional Diversity in the Mouse Kidney. Dev Cell. 2019; 51(3):399-413.e7. PMC: 6948019. DOI: 10.1016/j.devcel.2019.10.005. View

Zhao Z, Wu J, Xu H, Zhou C, Han B, Zhu H . XJB-5-131 inhibited ferroptosis in tubular epithelial cells after ischemia-reperfusion injury. Cell Death Dis. 2020; 11(8):629. PMC: 7429848. DOI: 10.1038/s41419-020-02871-6. View

Fu Y, Tang C, Cai J, Chen G, Zhang D, Dong Z . Rodent models of AKI-CKD transition. Am J Physiol Renal Physiol. 2018; 315(4):F1098-F1106. PMC: 6230729. DOI: 10.1152/ajprenal.00199.2018. View

10.

Alim I, Caulfield J, Chen Y, Swarup V, Geschwind D, Ivanova E . Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell. 2019; 177(5):1262-1279.e25. DOI: 10.1016/j.cell.2019.03.032. View

11.

Cho E, PATTERSON L, Brookhiser W, Mah S, Kintner C, Dressler G . Differential expression and function of cadherin-6 during renal epithelium development. Development. 1998; 125(5):803-12. DOI: 10.1242/dev.125.5.803. View

12.

Ide S, Yahara Y, Kobayashi Y, Strausser S, Ide K, Watwe A . Yolk-sac-derived macrophages progressively expand in the mouse kidney with age. Elife. 2020; 9. PMC: 7205460. DOI: 10.7554/eLife.51756. View

13.

Linkermann A, Skouta R, Himmerkus N, Mulay S, Dewitz C, De Zen F . Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014; 111(47):16836-41. PMC: 4250130. DOI: 10.1073/pnas.1415518111. View

14.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

15.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

16.

Wilson P, Wu H, Kirita Y, Uchimura K, Ledru N, Rennke H . The single-cell transcriptomic landscape of early human diabetic nephropathy. Proc Natl Acad Sci U S A. 2019; 116(39):19619-19625. PMC: 6765272. DOI: 10.1073/pnas.1908706116. View

17.

Carbon S, Ireland A, Mungall C, Shu S, Marshall B, Lewis S . AmiGO: online access to ontology and annotation data. Bioinformatics. 2008; 25(2):288-9. PMC: 2639003. DOI: 10.1093/bioinformatics/btn615. View

18.

Daniels B, Snyder A, Olsen T, Orozco S, Oguin 3rd T, Tait S . RIPK3 Restricts Viral Pathogenesis via Cell Death-Independent Neuroinflammation. Cell. 2017; 169(2):301-313.e11. PMC: 5405738. DOI: 10.1016/j.cell.2017.03.011. View

19.

Choi J, Park J, Tsagkogeorga G, Yanagita M, Koo B, Han N . Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration. Cell Stem Cell. 2020; 27(3):366-382.e7. PMC: 7487779. DOI: 10.1016/j.stem.2020.06.020. View

20.

Strunz M, Simon L, Ansari M, Kathiriya J, Angelidis I, Mayr C . Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat Commun. 2020; 11(1):3559. PMC: 7366678. DOI: 10.1038/s41467-020-17358-3. View