期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-021-24712-6
关键词
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资金
- Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany
- international research training group (IRTG) [2251]
- German Research Foundation (DFG) [324141047, GE2845/1-1, AN372/24-1, KR3363/3-1]
- transCampus initiative of S.R.B
- DFG [CO 291/5-2, CO 291/7-1, PR 1752/3-1]
- German Federal Ministry of Education and Research (BMBF) VIP + program [03VP04260]
- Helmholtz Validation Fund [0042]
- Ministry of Science and Higher Education of the Russian Federation [075-15-2019-1933]
- Else Kroner-Fresenius-Stiftung
- Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi)
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [GA 884754]
- [SFB-TRR 205]
- [SFB-TRR 127]
- [SPP2306]
- [SFB 1350 TP C2]
This study demonstrates the role of ferroptosis in acute kidney injury and how dysfunction of Gpx4 can hypersensitize mice to tubular damage. The researchers developed a dual inhibitor targeting RIPK1 and ferroptosis, which improved survival rates in mouse models of acute kidney injury.
Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4(cys/-)) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis. Necroptosis, a form of cell death, occurs in acute renal injury. Here, the authors show that ferroptosis-a form of cell death dependent on iron - also occurs during acute kidney injury, and show that an inhibitor of ferroptosis can improve survival in a mouse model of acute kidney damage.
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