Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells

Martín‐Sánchez, Diego; Gallegos-Villalobos, Ángel; Fontecha‐Barriuso, Miguel; Carrasco, Susana; Sanchez-Niño, María Dolores; López-Hernández, Francisco J.; Ruíz-Ortega, Marta; Egido, Jesús; Ortíz, Alberto; Sanz, Ana B.

doi:10.1038/srep41510

Cited by 30 publications

(21 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…mice ( Figure 2 D). Interestingly, dysregulation of Fe/heme metabolism in HSCs leads to oxidative stress through free radical generation (e.g., H 2 O 2 ) and HSC ablation ( Muto et al., 2017 ), whereas reduction in the cellular iron pool causes mitochondrial dysfunction and myeloid cell death ( al-Rafaie et al., 1994 ; Martin-Sanchez et al., 2017 ). Thus, we postulated that Mtb disrupts Fe metabolism to limit myelopoiesis.…”

Section: Resultsmentioning

confidence: 99%

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

Khan

Downey

Sanz

et al. 2020

Cell

161

179

View full text Add to dashboard Cite

Summary A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis ( Mtb ). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb . Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb . Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.

show abstract

Section: Resultsmentioning

confidence: 99%

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

Khan

Downey

Sanz

et al. 2020

Cell

161

179

View full text Add to dashboard Cite

show abstract

“…In this study, results showed that cell death occurred due to apoptosis as well as necrosis. It was also found that the drug toxicity depends on its action mechanism, because it depends on the iron depletion-induced downregulation of BclxL [26]. Deferasirox caused the loss of mitochondrial membrane potential, and cytochrome c was released from mitochondria in a time-dependent manner [26].…”

Section: Discussionmentioning

confidence: 99%

Early Kidney Damage Markers after Deferasirox Treatment in Patients with Thalassemia Major: A Case-Control Study

Badeli

Baghersalimi

Eslami

et al. 2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Background. The life of patients with β-thalassemia major depends on blood transfusion. Regular blood transfusion leads to hemosiderosis in their main organs. The aim of this study was to compare the effects of deferasirox and deferoxamine on renal damage in patients with β-thalassemia major. Method. The present case-control study was conducted on 60 individuals who were referred to the 17th Shahrivar Tertiary Referral Hospital in Guilan province, Iran. In this study, patients with β-thalassemia major who used deferasirox (n=21) and patients who used deferoxamine (n=19) were evaluated. The control group (n=20) was selected from healthy individuals. Serum creatinine (CREA), blood urea nitrogen (BUN), and Cystatin C were measured from blood samples. Furthermore, urinary (U.) neutrophil gelatinase-associated lipocalin (NGAL), albumin (Alb), interleukin- (IL-) 18, and Kidney Injury Molecule-1 (KIM-1) were measured by the ELISA method and normalized for U. creatinine (CREA). Results. U. NGAL, U. IL-18, and BUN biomarkers in the deferasirox group were significantly higher than those in the control group (p<0.001). U. NGAL/CREA and U. KIM-1/CREA ratios increased in both the deferoxamine and deferasirox groups compared to the control group (p<0.05). U. Alb was significantly higher in patients treated with deferoxamine than in healthy participants (p<0.05). Conclusion. The findings of this study indicate that after taking deferasirox, there was renal damage and an increase in inflammatory factors. Also, minor renal impairment was observed after deferoxamine administration, but it was not confirmed at the molecular level (U. NGAL and KIM-1). Therefore, it seems that patients who are taking these two drugs should be monitored carefully.

show abstract

“…The pathophysiological relevance of necroptosis has been demonstrated in diverse preclinical models of disease, including acute kidney injury 13 – 18 as recently reviewed 19 . Ferroptosis also contributes to injury to the kidney and other organs 20 – 23 . However, definitive proof of their role in human disease requires interventional studies specifically targeting these cell death pathways, which have not been performed yet.…”

Section: Cell Death Mechanismsmentioning

confidence: 99%

Cell death-based approaches in treatment of the urinary tract-associated diseases: a fight for survival in the killing fields

et al. 2018

Self Cite

View full text Add to dashboard Cite

Urinary tract-associated diseases comprise a complex set of disorders with a variety of etiologic agents and therapeutic approaches and a huge global burden of disease, estimated at around 1 million deaths per year. These diseases include cancer (mainly prostate, renal, and bladder), urinary tract infections, and urolithiasis. Cell death plays a key role in the pathogenesis and therapy of these conditions. During urinary tract infections, invading bacteria may either promote or prevent host cell death by interfering with cell death pathways. This has been studied in detail for uropathogenic E. coli (UPEC). Inhibition of host cell death may allow intracellular persistence of live bacteria, while promoting host cell death causes tissue damage and releases the microbes. Both crystals and urinary tract obstruction lead to tubular cell death and kidney injury. Among the pathomechanisms, apoptosis, necroptosis, and autophagy represent key processes. With respect to malignant disorders, traditional therapeutic efforts have focused on directly promoting cancer cell death. This may exploit tumor-specific characteristics, such as targeting Vascular Endothelial Growth Factor (VEGF) signaling and mammalian Target of Rapamycin (mTOR) activity in renal cancer and inducing survival factor deprivation by targeting androgen signaling in prostate cancer. An area of intense research is the use of immune checkpoint inhibitors, aiming at unleashing the full potential of immune cells to kill cancer cells. In the future, this may be combined with additional approaches exploiting intrinsic sensitivities to specific modes of cell death such as necroptosis and ferroptosis. Here, we review the contribution of diverse cell death mechanisms to the pathogenesis of urinary tract-associated diseases as well as the potential for novel therapeutic approaches based on an improved molecular understanding of these mechanisms.

show abstract

Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells

Cited by 30 publications

References 53 publications

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

Early Kidney Damage Markers after Deferasirox Treatment in Patients with Thalassemia Major: A Case-Control Study

Cell death-based approaches in treatment of the urinary tract-associated diseases: a fight for survival in the killing fields

Contact Info

Product

Resources

About