Synchronized renal tubular cell death involves ferroptosis
2014
Linkermann, Andreas | Skouta, Rachid | Himmerkus, Nina | Mulay, Shrikant R. | Dewitz, Christin | De Zen, Federica | Prokai, Agnes | Zuchtriegel, Gabriele | Krombach, Fritz | Welz, Patrick-Simon | Weinlich, Ricardo | Vanden Berghe, Tom | Vandenabeele, Peter | Pasparakis, Manolis | Bleich, Markus | Weinberg, Joel M. | Reichel, Christoph A. | Bräsen, Jan Hinrich | Kunzendorf, Ulrich | Anders, Hans-Joachim | Stockwell, Brent R. | Green, Douglas R. | Krautwald, Stefan
Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia–reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury. To suppress ferroptosis in vivo, we generated a novel third-generation ferrostatin (termed 16-86), which we demonstrate to be more stable, to metabolism and plasma, and more potent, compared with the first-in-class compound ferrostatin-1 (Fer-1). Even in conditions with extraordinarily severe IRI, 16-86 exerts strong protection to an extent which has not previously allowed survival in any murine setting. In addition, 16-86 further potentiates the strong protective effect on IRI mediated by combination therapy with necrostatins and compounds that inhibit mitochondrial permeability transition. Renal tubules thus represent a tissue that is not sensitized to necroptosis by loss of FADD or caspase-8. Finally, ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins and by combination therapy.
Show more [+] Less [-]AGROVOC Keywords
Bibliographic information
This bibliographic record has been provided by National Agricultural Library