TNF-α-mediated cardiorenal injury after rhabdomyolysis in rats

Homsi, Eduardo; Andreazzi, Diego Duarte; Faria, José B. Lopes de; Janino, Patrícia

doi:10.1152/ajprenal.00311.2014

Cited by 37 publications

(20 citation statements)

References 42 publications

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“…In the same line, no MLKL phosphorylation was observed in Mb-stimulated renal cells, arguing against the occurrence of necroptosis under these conditions. However, these findings are discordant with those obtained by Homsi et al (46), showing a predominant role of necroptosis in tubular injury in rats with rhabdomyolysis, but with a lower dose of glycerol injected. In that study, the RIPK1 inhibitor Nec-1s reduced creatinine plasma levels and tubular necrosis (46).…”

Section: Discussionsupporting

confidence: 67%

“…However, these findings are discordant with those obtained by Homsi et al (46), showing a predominant role of necroptosis in tubular injury in rats with rhabdomyolysis, but with a lower dose of glycerol injected. In that study, the RIPK1 inhibitor Nec-1s reduced creatinine plasma levels and tubular necrosis (46). However, under certain circumstances, it has been suggested that Nec-1s may not be a selective inhibitor of necroptosis, because it may also inhibit ferroptosis (47,48).…”

Section: Discussionsupporting

confidence: 67%

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Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis‐mediated cell death

et al. 2019

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Acute kidney injury is a common complication of rhabdomyolysis. A better understanding of this syndrome may be useful to identify novel therapeutic targets because there is no specific treatment so far. Ferroptosis is an iron‐dependent form of regulated nonapoptotic cell death that is involved in renal injury. In this study, we investigated whether ferroptosis is associated with rhabdomyolysis‐mediated renal damage, and we studied the therapeutic effect of curcumin, a powerful antioxidant with renoprotective properties. Induction of rhabdomyolysis in mice increased serum creatinine levels, endothelial damage, inflammatory chemokines, and cytokine expression, alteration of redox balance (increased lipid peroxidation and decreased antioxidant defenses), and tubular cell death. Treatment with curcumin initiated before or after rhabdomyolysis induction ameliorated all these pathologic and molecular alterations. Although apoptosis or receptor‐interacting protein kinase (RIPK)3‐mediated necroptosis were activated in rhabdomyolysis, our results suggest a key role of ferroptosis. Thus, treatment with ferrostatin 1, a ferroptosis inhibitor, improved renal function in glycerol‐injected mice, whereas no beneficial effects were observed with the pan‐caspase inhibitor carbobenzoxy‐valyl‐alanyl‐aspartyl‐(O‐methyl)‐fluoromethylketone or in RIPK3‐deficient mice. In cultured renal tubular cells, myoglobin (Mb) induced ferroptosis‐sensitive cell death that was also inhibited by curcumin. Mechanistic in vitro studies showed that curcumin reduced Mb‐mediated inflammation and oxidative stress by inhibiting the TLR4/NF‐κB axis and activating the cytoprotective enzyme heme oxygenase 1. Our findings are the first to demonstrate the involvement of ferroptosis in rhabdomyolysis‐associated renal damage and its sensitivity to curcumin treatment. Therefore, curcumin may be a potential therapeutic approach for patients with this syndrome.—Guerrero‐Hue, M., García‐Caballero, C., Palomino‐Antolín, A., Rubio‐Navarro, A., Vázquez‐Carballo, C., Herencia, C., Martín‐Sanchez, D., Farré‐Alins, V., Egea, J., Cannata, P., Praga, M., Ortiz, A., Egido, J., Sanz, A. B., Moreno, J. A. Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis‐mediated cell death. FASEB J. 33,8961–8975 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 67%

Section: Discussionsupporting

confidence: 67%

Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis‐mediated cell death

et al. 2019

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“…11,[24][25][26] However, necroptosis may not be the main tubular cell death pathway in ischemia-reperfusion injury, where the beneficial effect of necroptosis inhibitors may be because of endothelial protection. Recently, regulated necrosis pathways, such as necroptosis and ferroptosis, were proposed to have a key role in acute renal injury.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid–Induced AKI

Martín‐Sánchez¹,

Ruiz‐Andrés²,

Poveda³

et al. 2016

JASN

433

382

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AKI is histologically characterized by necrotic cell death and inflammation. Diverse pathways of regulated necrosis have been reported to contribute to AKI, but the molecular regulators involved remain unclear. We explored the relative contributions of ferroptosis and necroptosis to folic acid (FA)-induced AKI in mice. FA-AKI in mice associates with lipid peroxidation and downregulation of glutathione metabolism proteins, features that are typical of ferroptotic cell death. We show that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, preserved renal function and decreased histologic injury, oxidative stress, and tubular cell death in this model. With respect to the immunogenicity of ferroptosis, Fer-1 prevented the upregulation of IL-33, an alarmin linked to necroptosis, and other chemokines and cytokines and prevented macrophage infiltration and Klotho downregulation. In contrast, the pancaspase inhibitor zVAD-fmk did not protect against FA-AKI. Additionally, although FA-AKI resulted in increased protein expression of the necroptosis mediators receptor-interacting protein kinase 3 (RIPK3) and mixed lineage domain-like protein (MLKL), targeting necroptosis with the RIPK1 inhibitor necrostatin-1 or genetic deficiency of RIPK3 or MLKL did not preserve renal function. Indeed, compared with wild-type mice, MLKL knockout mice displayed more severe AKI. However, RIPK3 knockout mice with AKI had less inflammation than their wild-type counterparts, and this effect associated with higher IL-10 concentration and regulatory T cell-to-leukocyte ratio in RIPK3 knockout mice. These data suggest that ferroptosis is the primary cause of FA-AKI and that immunogenicity secondary to ferroptosis may further worsen the damage, although necroptosis-related proteins may have additional roles in AKI.

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“…The same process causes tubular necrosis in rhabdomyolysis. 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.…”

Section: Sepsis Urosepsismentioning

confidence: 99%

Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

Journal of the American Society of Nephrology

208

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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TNF-α-mediated cardiorenal injury after rhabdomyolysis in rats

Cited by 37 publications

References 42 publications

Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis‐mediated cell death

Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis‐mediated cell death

Ferroptosis, but Not Necroptosis, Is Important in Nephrotoxic Folic Acid–Induced AKI

Necroinflammation in Kidney Disease

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