Role of Annexin A5 in Cisplatin-induced Toxicity in Renal Cells

Jeong, Jin-Joo; Park, Nahee; Kwon, Yeo‐Jung; Ye, Dong-Jin; Moon, Aree; Chun, Young‐Jin

doi:10.1074/jbc.m113.450163

Cited by 43 publications

(33 citation statements)

References 36 publications

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“…. Research over the past few years has gained significant insights into the mechanisms regarding cisplatin nephrotoxicity, which mainly involved apoptosis, inflammation and oxidative stress et al 171819202122…”

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confidence: 99%

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Zhang

Chen

Huang

et al. 2017

Sci Rep

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Nephrotoxicity has long been the most severe and life-threatening side-effect of cisplatin, whose anticancer effect is therefore restricted. Previous pathological studies have shown that both renal cortex and medulla could be injured by cisplatin. Our TUNEL (terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling) assay results further uncovered that medulla subjected more severe injury than cortex. In order to depict the underlying metabolic mechanism of spatial difference in response to cisplatin, in the present study, mass spectrometry-based untargeted metabolomics approach was applied to profile renal cortex and medulla metabolites of rat after receiving a single dose of cisplatin (2.5, 5 or 10 mg/kg). Eventually, 53 and 55 differential metabolites in cortex and medulla were screened out, respectively. Random forest, orthogonal partial least squares-discriminant analysis and metabolic cumulative fold change analysis revealed that metabolic changes in medulla were more obviously dose-dependent than those in cortex, which confirmed the conclusion that medulla was more sensitive to cisplatin exposure. Furthermore, 29 intermediates were recognized as the most contributive metabolites for the sensitivity difference. Metabolic pathways interrupted by cisplatin mainly included amino acid, energy, lipid, pyrimidine, purine, and creatine metabolism. Our findings provide new insight into the mechanism study of cisplatin-induced nephrotoxicity.Cisplatin [cis-diamminedichloroplatinum(II)] is an effective antineoplastic agent that was widely applied in the treatment of various types of solid tumors in the past several decades 1-3 . However, due to poor selectivity, cisplatin could cause neurotoxicity, nephrotoxicity, nausea and vomiting, and ototoxicity et al. in clinical [4][5][6][7][8][9][10] . As the principal excretory organ for cisplatin, kidney accumulates and retains platinum to a greater degree than other organs 11,12 . Therefore, nephrotoxicity has long been the most severe and life-threatening toxicity among these side-effects 13,14 . Statistics showed there were about 25-35% patients experienced a significant decline in renal function after receiving a single dose of cisplatin 13,15 . The declines manifested clinically as lower glomerular filtration rate, reduced serum magnesium and potassium levels et al. 13,16 . Research over the past few years has gained significant insights into the mechanisms regarding cisplatin nephrotoxicity, which mainly involved apoptosis, inflammation and oxidative stress et al. [17][18][19][20][21][22] . However, how the toxicity occurs and develops, and how various types of mechanisms are integrated to induce distinct kidney pathology, remain largely unknown.Metabolomics is an emerging -omics approach that could provide information of holistic and time-dependent metabolic variation in response to xenobiotic interventions 23,24 . At present, metabolomics analysis encompasses different strategies depending on the objective of study, namely target analysis of a group of c...

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confidence: 99%

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Zhang

Chen

Huang

et al. 2017

Sci Rep

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“…Recently, Jeong et al (2014) and Kwon et al (2013) reported that annexin A5 plays an important role in cisplatin-induced mitochondriadependent apoptosis via oligomerization of VDAC. In the present study, an important role for annexin A5 was further confirmed in mitochondria-dependent apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, it was reported that annexin A5 plays an important role in cisplatininduced mitochondria-dependent apoptosis in renal cells (Jeong et al, 2014;Kwon et al, 2013). To determine whether annexin A5 participated in auranofin-induced mitochondriadependent apoptosis, changes in annexin A5 mRNA and protein expression were measured.…”

Section: Auranofin Induces Expression Of Annexin A5 and Translocationmentioning

confidence: 99%

“…Recently, data demonstrated that annexin A5 plays an important role in cisplatin-induced toxicity by mediating the mitochondrial apoptotic pathway via the induction and oligomerization of the voltage-dependent anion channel (VDAC) (Jeong et al, 2014;Kwon et al, 2013). Cisplatin is a well-known gold compound that induces mitochondria-dependent apoptosis (Xiao et al, 2003;Kim and Moon, 2012;Carvalho Rodrigues et al, 2012).…”

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Auranofin Promotes Mitochondrial Apoptosis by Inducing Annexin A5 Expression and Translocation in Human Prostate Cancer Cells

Park

Chun

2014

Journal of Toxicology and Environmental Health, Part A

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Auranofin is a lipophilic gold compound with anti-inflammatory and immunosuppressive properties. This compound also exerts antiproliferative effects in several human cancer cell lines. Although auranofin induces apoptosis in human cancer cells, the underlying mechanisms remain unclear. This study investigated auranofin-mediated inhibition of cell growth and induction of mitochondrial apoptosis in PC3 human prostate cancer cells. Treatment with auranofin significantly inhibited cell viability with an IC50 value of 2.5 μM after 24 h. In particular, when cells were treated with 2.5 μM auranofin, there was a 2.2-fold increase in apoptotic cells compared to untreated cells. Auranofin activated caspase-3 and -8 in a concentration-dependent manner and decreased the levels of mitochondrial anti-apoptotic factors, such as Bcl-2 and Bcl-xL. In addition, auranofin enhanced oligomerization of the voltage-dependent anion channel (VDAC) in a concentration- and time-dependent manner. Interestingly, auranofin significantly enhanced annexin A5 mRNA and protein expression and promoted annexin A5 translocation into the mitochondria. In order to characterize the function of annexin A5 in auranofin-induced mitochondrial apoptosis, annexin A5 was depleted using siRNA. Annexin A5 siRNA suppressed auranofin-mediated annexin A5 expression and VDAC oligomerization. Accordingly, annexin A5 depletion rescued auranofin-induced apoptosis, which may be mediated by caspase-3 activation. In conclusion, the present findings suggest that auranofin induces mitochondrial apoptosis through induction of annexin A5 expression and translocation as well as VDAC oligomerization in human prostate cancer cells.

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“…Deletion of VDAC3 increases mitochondrial production of the reactive oxygen species, alters renal sodium transport, and leads to hypertension whereas deletion of VDAC2 is lethal during embryonic development [28,29]. Oligomerization of VDAC1 has been implicated in cisplatin-induced apoptosis and nephrotoxicity due to a formation of pores in the outer mitochondrial membrane that allow for the escape of cytochrome c from the mitochondrial intermembrane space to the cytosol [30]. As VDAC1 conductance can differentially mitigate or exacerbate pathological conditions in different organs and cell types, the purpose of this study was to determine the role of VDAC1 in (1) ischemia-induced mitochondrial dysfunction and injury to the kidney, and (2) kidney repair after ischemia.…”

Section: Introductionmentioning

confidence: 99%

Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury

Nowak

Megyesi

Craigen³

2020

Biomolecules

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Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and FoF1-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and FoF1-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI.

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Role of Annexin A5 in Cisplatin-induced Toxicity in Renal Cells

Cited by 43 publications

References 36 publications

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Auranofin Promotes Mitochondrial Apoptosis by Inducing Annexin A5 Expression and Translocation in Human Prostate Cancer Cells

Deletion of VDAC1 Hinders Recovery of Mitochondrial and Renal Functions After Acute Kidney Injury

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