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 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85111097567&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-24712-6
DO - 10.1038/s41467-021-24712-6
M3 - Article
C2 - 34285231
AN - SCOPUS:85111097567
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4402
ER -