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

Guerrero‐Hue, Melania; García‐Caballero, Cristina; Palomino-Antolín, Alejandra; Rubio‐Navarro, Alfonso; Vázquez‐Carballo, Cristina; Herencia, Carmen; Martín‐Sánchez, Diego; Farré‐Alins, Víctor; Egea, Javier; Cannata, Pablo; Praga, Manuel; Ortíz, Alberto; Egido, Jesús; Sanz, Ana B.; Moreno, Juan Antonio

doi:10.1096/fj.201900077r

Cited by 192 publications

(139 citation statements)

References 61 publications

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“…Ramesh G et al have reported that cisplatin could induce both apoptosis and necrosis which is mediated by TNF receptor 2 (TNFR2) in mice AKI model 17 . In recent years, researches have showed that ferroptosis is playing an emerging role in clinical AKI as well as rodent models induced by IRI and rhabdomyolysis 18,19 . Earlier before two decades, Baliga et al's work has suggested the importance of ferric ion in pathological processes of cisplatin induced renal injury in mice 8 .…”

Section: Discussionmentioning

confidence: 99%

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

et al. 2020

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Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.

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Section: Discussionmentioning

confidence: 99%

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

et al. 2020

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“…Ischemia/reperfusion renal injury is the leading cause of ARF, a disease with high morbidity and mortality because of the lack of effective treatment 9 , 38 . Renal tubular cell death induced by I/R was considered as the main cause of ARF 19 , 46 . In the present study, we confirmed the occurrence of I/R-induced ferroptosis in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Acyl-CoA synthetase long-chain family member 4 (ACSL4) dictates ferroptosis sensitivity by shaping cellular lipid composition 18 . Recent studies have revealed that ferroptosis plays an important role in rhabdomyolysis-associated renal damage and severe acute pancreatitis (SAP) induced acute kidney injury 19 , 20 . Ferroptosis mediates postischemic and toxic renal necrosis, which may be therapeutically targeted by ferrostatins 21 , indicating that ferroptosis may play central roles in the pathogenesis of renal I/R injury.…”

Section: Introductionmentioning

confidence: 99%

miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

et al. 2020

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Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

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“…Following polymer and/ or linker degradation, the drug is then released to the cytosol 45 . Of note, lysosomal cathepsins are involved in lysosome-mediated apoptosis in several pathological processes including renal diseases and AKI, and, as recently reported, in ferroptosis 49,50 . Moreover, previous studies have revealed that curcumin restrains the leakage of hydrolases by an effect that depends on the lysosomal membrane stabilization 51 .…”

Section: Discussionmentioning

confidence: 61%

Effective Nephroprotection Against Acute Kidney Injury with a Star-Shaped Polyglutamate-Curcuminoid Conjugate

Córdoba-David

Duro‐Castaño

Castelo‐Branco

et al. 2020

Sci Rep

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The lack of effective pharmacological treatments for acute kidney injury (AKI) remains a significant public health problem. Given the involvement of apoptosis and regulated necrosis in the initiation and progression of AKI, the inhibition of cell death may contribute to AKI prevention/recovery. Curcuminoids are a family of plant polyphenols that exhibit attractive biological properties that make them potentially suitable for AKI treatment. Now, in cultured tubular cells, we demonstrated that a crosslinked self-assembled star-shaped polyglutamate (PGA) conjugate of bisdemethoxycurcumin (St-PGA-CL-BDMC) inhibits apoptosis and necroptosis induced by Tweak/TNFα/IFNγ alone or concomitant to caspase inhibition. St-PGA-CL-BDMC also reduced NF-κB activation and subsequent gene transcription. In vivo, St-PGA-CL-BDMC prevented renal cell loss and preserved renal function in mice with folic acid-induced AKI. Mechanistically, St-PGA-CL-BDMC inhibited AKI-induced apoptosis and expression of ferroptosis markers and also decreased the kidney expression of genes involved in tubular damage and inflammation, while preserving the kidney expression of the protective factor, Klotho. Thus, due to renal accumulation and attractive pharmacological properties, the application of PGAbased therapeutics may improve nephroprotective properties of current AKI treatments. Acute kidney injury (AKI) involves a sudden and generally transient loss of glomerular filtration leading to the retention of damaging nitrogenous byproducts normally excreted in the urine. Independently of its etiology, AKI usually implies extensive renal parenchymal injury, which, in the case of unsuccessful repair, favors the progression of AKI to chronic kidney disease (CKD). The mortality of AKI may be as high as 50%, and currently, there exist no specific therapies to attenuate AKI or accelerate recovery beyond dialysis 1. Thus, there is an unmet clinical need for novel AKI treatments. During the initial stages of AKI, proximal renal tubular cell death triggers a cascade of damaging events, including inflammation, that amplifies kidney injury 2,3. Thus, the control and execution of apoptosis and several kinds of regulated necrosis depend on environmental conditions as well as on the recruitment of intracellular cell death pathways. Distinct forms of cell death are amenable to pharmacological modulation. Strategies to specifically inhibit caspases, the final executioners of apoptosis, decrease apoptosis, inflammation, and improve renal function in experimental ischemia/reperfusion or septic AKI 4,5. However, the inhibition of overall caspase activity failed to improve nephrotoxic AKI 6. In this regard, caspase activation is involved in cellular events beyond cell death regulation, including, among others, cell cycle and the regulation of proliferation 7,8. Strategies that interfere with initial or intermediate regulators of caspase activity, like protein kinases, survival factors, cytokine death receptors, oxidative stress factors, apoptosome factors, and tumor-suppresso...

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

Cited by 192 publications

References 61 publications

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

Effective Nephroprotection Against Acute Kidney Injury with a Star-Shaped Polyglutamate-Curcuminoid Conjugate

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