Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury

Wulf Tonnus; Claudia Meyer; Christian Steinebach; Alexia Belavgeni; Anne von Mässenhausen; Nadia Zamora Gonzalez; Francesca Maremonti; Florian Gembardt; Nina Himmerkus; Markus Latk; Sophie Locke; Julian Marschner; Wenjun Li; Spencer Short; Sebastian Doll; Irina Ingold; Bettina Proneth; Christoph Daniel; Nazanin Kabgani; Rafael Kramann; Stephen Motika; Paul J. Hergenrother; Stefan R. Bornstein; Christian Hugo; Jan Ulrich Becker; Kerstin Amann; Hans Joachim Anders; Daniel Kreisel; Derek Pratt; Michael Gütschow; Marcus Conrad; Andreas Linkermann

doi:10.1038/s41467-021-24712-6

Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury

Wulf Tonnus, Claudia Meyer, Christian Steinebach, Alexia Belavgeni, Anne von Mässenhausen, Nadia Zamora Gonzalez, Francesca Maremonti, Florian Gembardt, Nina Himmerkus, Markus Latk, Sophie Locke, Julian Marschner, Wenjun Li, Spencer Short, Sebastian Doll, Irina Ingold, Bettina Proneth, Christoph Daniel, Nazanin Kabgani, Rafael KramannStephen Motika, Paul J. Hergenrother, Stefan R. Bornstein, Christian Hugo, Jan Ulrich Becker, Kerstin Amann, Hans Joachim Anders, Daniel Kreisel, Derek Pratt, Michael Gütschow, Marcus Conrad, Andreas Linkermann^*

^*Corresponding author for this work

Internal Medicine

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Article number	4402
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-24712-6
Publication status	Published - 20 Jul 2021

Bibliographical note

Funding Information:
We would like to cordially thank Cemile Jakupoglu and Markus Brielmeier for help in generating the Fsp1−/−-mice, Romy Opitz for expert technical assistance, and Renata Drtina for critically reading the manuscript. We thank the histology facility, the FACS facility, as well as the light microscopy facility at the CMCB Dresden, in particular Hella Hartmann, for the expert help. Work in the Linkermann Lab is funded by the Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany, and supported by the SFB-TRR 205, SFB-TRR 127, SPP2306, and the international research training group (IRTG) 2251. This work was supported by the German Research Foundation (DFG) (Heisenberg-Professorship to A.L. (project number 324141047), GE2845/1-1 to F.G., AN372/24-1 to H.J.A. and KR3363/3-1 to N.K.). We received further funding for this project from the transCampus initiative of S.R.B. Work in the Conrad Lab is funded by the DFG (CO 291/5-2; CO 291/7-1; PR 1752/3-1), the German Federal Ministry of Education and Research (BMBF) VIP + program 03VP04260, the Helmholtz Validation Fund (0042), the Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1933), the Else Kröner-Fresenius-Stiftung, the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi), and M.C. has further received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. GA 884754). K.A. and C.D. received funding by the SFB 1350 TP C2.

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© 2021, The Author(s).

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Tonnus, W., Meyer, C., Steinebach, C., Belavgeni, A., von Mässenhausen, A., Gonzalez, N. Z., Maremonti, F., Gembardt, F., Himmerkus, N., Latk, M., Locke, S., Marschner, J., Li, W., Short, S., Doll, S., Ingold, I., Proneth, B., Daniel, C., Kabgani, N., ... Linkermann, A. (2021). Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nature Communications, 12(1), [4402]. https://doi.org/10.1038/s41467-021-24712-6

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title = "Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury",

abstract = "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 (Gpx4cys/-) 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.",

author = "Wulf Tonnus and Claudia Meyer and Christian Steinebach and Alexia Belavgeni and {von M{\"a}ssenhausen}, Anne and Gonzalez, {Nadia Zamora} and Francesca Maremonti and Florian Gembardt and Nina Himmerkus and Markus Latk and Sophie Locke and Julian Marschner and Wenjun Li and Spencer Short and Sebastian Doll and Irina Ingold and Bettina Proneth and Christoph Daniel and Nazanin Kabgani and Rafael Kramann and Stephen Motika and Hergenrother, {Paul J.} and Bornstein, {Stefan R.} and Christian Hugo and Becker, {Jan Ulrich} and Kerstin Amann and Anders, {Hans Joachim} and Daniel Kreisel and Derek Pratt and Michael G{\"u}tschow and Marcus Conrad and Andreas Linkermann",

note = "Funding Information: We would like to cordially thank Cemile Jakupoglu and Markus Brielmeier for help in generating the Fsp1−/−-mice, Romy Opitz for expert technical assistance, and Renata Drtina for critically reading the manuscript. We thank the histology facility, the FACS facility, as well as the light microscopy facility at the CMCB Dresden, in particular Hella Hartmann, for the expert help. Work in the Linkermann Lab is funded by the Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany, and supported by the SFB-TRR 205, SFB-TRR 127, SPP2306, and the international research training group (IRTG) 2251. This work was supported by the German Research Foundation (DFG) (Heisenberg-Professorship to A.L. (project number 324141047), GE2845/1-1 to F.G., AN372/24-1 to H.J.A. and KR3363/3-1 to N.K.). We received further funding for this project from the transCampus initiative of S.R.B. Work in the Conrad Lab is funded by the DFG (CO 291/5-2; CO 291/7-1; PR 1752/3-1), the German Federal Ministry of Education and Research (BMBF) VIP + program 03VP04260, the Helmholtz Validation Fund (0042), the Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1933), the Else Kr{\"o}ner-Fresenius-Stiftung, the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi), and M.C. has further received funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement No. GA 884754). K.A. and C.D. received funding by the SFB 1350 TP C2. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jul,

day = "20",

doi = "10.1038/s41467-021-24712-6",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Tonnus, W, Meyer, C, Steinebach, C, Belavgeni, A, von Mässenhausen, A, Gonzalez, NZ, Maremonti, F, Gembardt, F, Himmerkus, N, Latk, M, Locke, S, Marschner, J, Li, W, Short, S, Doll, S, Ingold, I, Proneth, B, Daniel, C, Kabgani, N, Kramann, R, Motika, S, Hergenrother, PJ, Bornstein, SR, Hugo, C, Becker, JU, Amann, K, Anders, HJ, Kreisel, D, Pratt, D, Gütschow, M, Conrad, M & Linkermann, A 2021, 'Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury', Nature Communications, vol. 12, no. 1, 4402. https://doi.org/10.1038/s41467-021-24712-6

TY - JOUR

T1 - Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury

AU - Tonnus, Wulf

AU - Meyer, Claudia

AU - Steinebach, Christian

AU - Belavgeni, Alexia

AU - von Mässenhausen, Anne

AU - Gonzalez, Nadia Zamora

AU - Maremonti, Francesca

AU - Gembardt, Florian

AU - Himmerkus, Nina

AU - Latk, Markus

AU - Locke, Sophie

AU - Marschner, Julian

AU - Li, Wenjun

AU - Short, Spencer

AU - Doll, Sebastian

AU - Ingold, Irina

AU - Proneth, Bettina

AU - Daniel, Christoph

AU - Kabgani, Nazanin

AU - Kramann, Rafael

AU - Motika, Stephen

AU - Hergenrother, Paul J.

AU - Bornstein, Stefan R.

AU - Hugo, Christian

AU - Becker, Jan Ulrich

AU - Amann, Kerstin

AU - Anders, Hans Joachim

AU - Kreisel, Daniel

AU - Pratt, Derek

AU - Gütschow, Michael

AU - Conrad, Marcus

AU - Linkermann, Andreas

N1 - Funding Information: We would like to cordially thank Cemile Jakupoglu and Markus Brielmeier for help in generating the Fsp1−/−-mice, Romy Opitz for expert technical assistance, and Renata Drtina for critically reading the manuscript. We thank the histology facility, the FACS facility, as well as the light microscopy facility at the CMCB Dresden, in particular Hella Hartmann, for the expert help. Work in the Linkermann Lab is funded by the Medical Clinic 3, University Hospital Carl Gustav Carus Dresden, Germany, and supported by the SFB-TRR 205, SFB-TRR 127, SPP2306, and the international research training group (IRTG) 2251. This work was supported by the German Research Foundation (DFG) (Heisenberg-Professorship to A.L. (project number 324141047), GE2845/1-1 to F.G., AN372/24-1 to H.J.A. and KR3363/3-1 to N.K.). We received further funding for this project from the transCampus initiative of S.R.B. Work in the Conrad Lab is funded by the DFG (CO 291/5-2; CO 291/7-1; PR 1752/3-1), the German Federal Ministry of Education and Research (BMBF) VIP + program 03VP04260, the Helmholtz Validation Fund (0042), the Ministry of Science and Higher Education of the Russian Federation (075-15-2019-1933), the Else Kröner-Fresenius-Stiftung, the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi), and M.C. has further received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. GA 884754). K.A. and C.D. received funding by the SFB 1350 TP C2. Publisher Copyright: © 2021, The Author(s).

PY - 2021/7/20

Y1 - 2021/7/20

N2 - 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 (Gpx4cys/-) 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.

AB - 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 (Gpx4cys/-) 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.

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U2 - 10.1038/s41467-021-24712-6

DO - 10.1038/s41467-021-24712-6

M3 - Article

AN - SCOPUS:85111097567

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4402

ER -

Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury

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