The RIP1-Kinase Inhibitor Necrostatin-1 Prevents Osmotic Nephrosis and Contrast-Induced AKI in Mice

Linkermann, Andreas; Heller, Jan Ole; Prókai, Ágnes; Weinberg, Joel M.; Zen, Federica De; Himmerkus, Nina; Szabó, Attila; Bräsen, Jan Hinrich; Kunzendorf, Ulrich; Krautwald, Stefan

doi:10.1681/asn.2012121169

Cited by 115 publications

(97 citation statements)

References 61 publications

(96 reference statements)

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“…The mode of cell death of tubular cells in acute kidney injury (AKI) has been a matter of intense discussion (21,22). Because RIPK3-deficient mice have been shown to be partially protected from IRI-induced tubular necrosis (4, 23) and because Nec-1 phenocopies this effect (21,24,25), it was hypothesized that necroptosis might be the mode of cell death that drives parenchymal cells into necrosis.…”

Section: Resultsmentioning

confidence: 99%

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Synchronized renal tubular cell death involves ferroptosis

Linkermann

Skouta

Himmerkus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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869

804

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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, irondependent 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 firstin-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.

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Section: Resultsmentioning

confidence: 99%

“…Using low-resolution intravital microscopy, we previously investigated the effects of Nec-1 on the diameter of peritubular capillaries (22). Using a similar approach with higher resolution (Fig.…”

Section: Ripk3-deficient Mice Exhibit Increased Renal Perfusion and Fmentioning

confidence: 99%

Synchronized renal tubular cell death involves ferroptosis

Linkermann

Skouta

Himmerkus

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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869

804

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“…Hence, inhibitors that can block necroptosis should prevent tissue injury and subsequent inflammatory responses. Indeed, the RIPK inhibitor Nec-1 was able to prevent organ injury in vivo in various studies (22,(23)(24)(25)(26)(27)48,56). Nec-1 or its derivers could therefore be a potent drug to prevent inflammation and rejection in transplantation.…”

Section: Discussionmentioning

confidence: 99%

RIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection

Pavlosky

Lau

et al. 2014

American Journal of Transplantation

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Cell death results in tissue damage and ultimately donor graft rejection and can occur as an active molecular process through apoptotic, necrotic and newly identified receptor interacting protein 1 and 3 kinase (RIPK1/3)-mediated necroptotic pathways. Necroptosis leads to the release of inflammatory molecules which can activate host immune cells. This pathway has yet to be studied in heart transplantation. We have found that necroptosis was induced in murine cardiac microvascular endothelial cell (MVEC) under anti-apoptotic condition following tumor necrosis factor alpha treatment. Necroptotic cell death and release of the danger molecule high mobility group box 1 (HMGB1) were inhibited by the RIPK1 inhibiting molecule necrostatin-1 and by genetic deletion of RIPK3. In addition, tissue necrosis, release of HMGB1 and graft cell infiltrate were attenuated in RIPK3 null heart allografts following transplantation. Finally, a brief sirolimus treatment markedly prolonged RIPK3 null cardiac allograft survival in allogeneic BALB/c recipients as compared to WT C57BL/6 donor grafts (95 AE 5.8 vs. 24 AE 2.6 days, p < 0.05). This study has demonstrated that RIPK1/3 contributes to MVEC death and cardiac allograft survival through necroptotic death and the release of danger molecules. Our results suggest that targeting RIPKmediated necroptosis may be an important therapeutic strategy in transplantation.

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“…82 In addition, contrast media-related renal dysfunction is entirely reversible by necrostatin-1. 83 Moderate-dose adriamycin-induced tubular necrosis and survival is attenuated in Ripk3-deficient mice, 84 but whether tubular cells themselves directly die via necroptosis, or succumb to some other cell death secondary to initial RIPK3-mediated hypoperfusion, is still a matter of debate. First, tubules cannot be sensitized to necroptosis by the loss of Fas-associated protein with death domain or caspase-8 35 ; second, necrostatins do not protect isolated renal tubules from ischemic injury.…”

Section: Sepsis Urosepsismentioning

confidence: 99%

Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

Journal of the American Society of Nephrology

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185

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The bidirectional causality between kidney injury and inflammation remains an area of unexpected discoveries. The last decade unraveled the molecular mechanisms of sterile inflammation, which established danger signaling via pattern recognition receptors as a new concept of kidney injury-related inflammation. In contrast, renal cell necrosis remained considered a passive process executed either by the complement-related membrane attack complex, exotoxins, or cytotoxic T cells. Accumulating data now suggest that renal cell necrosis is a genetically determined and regulated process involving specific outside-in signaling pathways. These findings support a unifying theory in which kidney injury and inflammation are reciprocally enhanced in an autoamplification loop, referred to here as necroinflammation. This integrated concept is of potential clinical importance because it offers numerous innovative molecular targets for limiting kidney injury by blocking cell death, inflammation, or both. Here, the contribution of necroinflammation to AKI is discussed in thrombotic microangiopathies, necrotizing and crescentic GN, acute tubular necrosis, and infective pyelonephritis or sepsis. Potential new avenues are further discussed for abrogating necroinflammation-related kidney injury, and questions and strategies are listed for further exploration in this evolving field.

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The RIP1-Kinase Inhibitor Necrostatin-1 Prevents Osmotic Nephrosis and Contrast-Induced AKI in Mice

Cited by 115 publications

References 61 publications

Synchronized renal tubular cell death involves ferroptosis

Synchronized renal tubular cell death involves ferroptosis

RIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection

Necroinflammation in Kidney Disease

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