scholarly journals Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway

2009 ◽  
Vol 296 (5) ◽  
pp. F983-F993 ◽  
Author(s):  
Man Jiang ◽  
Cong-Yi Wang ◽  
Shuang Huang ◽  
Tianxin Yang ◽  
Zheng Dong
Keyword(s):  
Cytochrome C ◽  
Primary Cultures ◽  
Mitochondrial Pathway ◽  
Limiting Factor ◽  
Double Knockout ◽  
Cytochrome C Release ◽  
Renal Tubular Cells ◽  
In The Wild ◽  
Renal Tubular ◽  
Induced Apoptosis

Nephrotoxicity is the major limiting factor for the use of cisplatin in cancer therapy. Recent studies have demonstrated an important role for p53 in cisplatin-induced renal injury. Nevertheless, pharmacological and genetic blockade of p53 only provides partial renoprotective effects, suggesting the presence of p53-independent injury mechanisms. To understand the p53-independent mechanisms, we have now examined cisplatin-induced apoptosis in p53-deficient kidney cells. We show that cisplatin could induce Bax activation, cytochrome c release, and apoptosis in primary cultures of p53-deficient renal tubular cells, albeit at a level that was lower than in the wild-type cells. Cisplatin could also induce typical apoptosis in p53-deficient baby mouse kidney (BMK) cells. The apoptosis was caspase dependent and could be completely blocked by general caspase inhibitors. Bax and Bak, two key molecules in the mitochondrial pathway of apoptosis, were interdependently activated by cisplatin, with Bax translocation to and Bax/Bak oligomerization in mitochondria, leading to cytochrome c release. Importantly, cytochrome c release and apoptosis were diminished in Bax/Bak single or double-knockout BMK cells. Furthermore, overexpression of Bcl-2 could ameliorate cisplatin-induced cytochrome c release and apoptosis. Together, the results have demonstrated a p53-independent mechanism of cisplatin nephrotoxicity that involves the mitochondrial pathway of apoptosis.

scholarly journals Apoptosis of Growth Plate Chondrocytes Occurs through a Mitochondrial Pathway

2007 ◽  
Vol 77 (1) ◽  
pp. 129-134 ◽  
Author(s):  
Cristina C. Teixeira ◽  
Aida P. Padron Costas ◽  
Yelena Nemelivsky
Keyword(s):  
Cytochrome C ◽  
Growth Plate ◽  
Caspase 3 ◽  
Mitochondrial Pathway ◽  
Chondrocyte Apoptosis ◽  
Cytochrome C Release ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Viability ◽  
Induced Apoptosis ◽  
Free Media

Abstract Objective: To determine the role of mitochondria in chondrocyte apoptosis induced by inorganic phosphate (Pi). Materials and Methods: Chondrocytes isolated from the growth plates of chick embryo tibia were treated with Pi in serum-free media; chondrocyte viability, mitochondrial membrane potential, cytochrome c release from mitochondria, caspase 3 activity, endonuclease activity, and DNA fragmentation were investigated. Results: Exposure to Pi for 24 hours induced apoptosis in growth plate chondrocytes through a pathway that involved loss of mitochondrial function, release of cytochrome c into the cytoplasm, increases in caspase 3 and endonuclease activities, and fragmentation of DNA. Conclusions: This study suggests that mitochondria are important players in Pi-induced apoptosis.

Inhibition of apoptosis by Zn2+ in renal tubular cells following ATP depletion

2004 ◽  
Vol 287 (3) ◽  
pp. F492-F500 ◽  
Author(s):  
Qingqing Wei ◽  
Jinzhao Wang ◽  
Mong-Heng Wang ◽  
Fushin Yu ◽  
Zheng Dong
Keyword(s):  
Cytochrome C ◽  
Renal Cell ◽  
Atp Depletion ◽  
Caspase Activation ◽  
Renal Protection ◽  
Cytochrome C Release ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Apoptosis has been implicated in ischemic renal injury. Thus one strategy of renal protection is to antagonize apoptosis. However, apoptosis inhibitory approaches remain to be fully explored. Zn2+ has long been implicated in apoptosis inhibition; but systematic analysis of the inhibitory effects of Zn2+ is lacking. Moreover, whether Zn2+ blocks renal cell apoptosis following ischemia is unknown. Here, we demonstrate that Zn2+ is a potent apoptosis inhibitor in an in vitro model of renal cell ischemia. ATP depletion induced apoptosis in cultured renal tubular cells, which was accompanied by caspase activation. Zn2+ at 10 μM inhibited both apoptosis and caspase activation, whereas Co2+ was without effect. In ATP-depleted cells, Zn2+ partially prevented Bax activation and cytochrome c release from mitochondria. In isolated cell cytosol, Zn2+ blocked cytochrome c-stimulated caspase activation at low-micromolar concentrations. In addition, Zn2+ could directly antagonize the enzymatic activity of purified recombinant caspases. We conclude that Zn2+ is a potent inhibitor of apoptosis in renal tubular cells following ATP depletion. Zn2+ blocks apoptosis at multiple steps including Bax activation, cytochrome c release, apoptosome function, and caspase activation.

Prevention of TNF-α-induced apoptosis in polyamine-depleted IEC-6 cells is mediated through the activation of ERK1/2

2004 ◽  
Vol 286 (3) ◽  
pp. G479-G490 ◽  
Author(s):  
Sujoy Bhattacharya ◽  
Ramesh M. Ray ◽  
Leonard R. Johnson
Keyword(s):  
Epithelial Cells ◽  
Cytochrome C ◽  
Critical Role ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Cytochrome C Release ◽  
Erk Phosphorylation ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Jnk Activation

It has been documented that polyamines play a critical role in the regulation of apoptosis in intestinal epithelial cells. We have recently reported that protection from TNF-α/cycloheximide (CHX)-induced apoptosis in epithelial cells depleted of polyamines is mediated through the inactivation of a proapoptotic mediator, JNK. In this study, we addressed the involvement of the MAPK pathway in the regulation of apoptosis after polyamine depletion of IEC-6 cells. Polyamine depletion by α-difluromethylornithine (DFMO) resulted in the sustained activation of ERK in response to TNF-α/CHX treatment. Pretreatment of polyamine-depleted IEC-6 cells with a cell membrane-permeable MEK1/2 inhibitor, U-0126, significantly inhibited TNF-α/CHX-induced ERK phosphorylation and significantly increased DNA fragmentation, JNK activity, and caspase-3 activity in response to TNF-α/CHX. Moreover, the dose dependency of U-0126-mediated inhibition of TNF-α/ CHX-induced ERK phosphorylation correlated with the reversal of the antiapoptotic effect of DFMO. IEC-6 cells expressing constitutively active MEK1 had decreased TNF-α/CHX-induced JNK phosphorylation and were significantly protected from apoptosis. Conversely, a dominant-negative MEK1 resulted in high basal activation of JNK, cytochrome c release, and spontaneous apoptosis. Polyamine depletion of the dominant-negative MEK1 cells did not prevent JNK activation or cytochrome c release and failed to confer protection from both TNF-α/CHX and camptothecin-induced apoptosis. Finally, expression of a dominant-negative mutant of JNK significantly protected IEC-6 cells from TNF-α/CHX-induced apoptosis. These data indicate that polyamine depletion results in the activation of ERK, which inhibits JNK activation and protects cells from apoptosis.

scholarly journals Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes

2015 ◽  
Vol 59 (12) ◽  
pp. 7489-7496 ◽  
Author(s):  
Bo Yun ◽  
Mohammad A. K. Azad ◽  
Cameron J. Nowell ◽  
Roger L. Nation ◽  
Philip E. Thompson ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Rat Kidney ◽  
Antimicrobial Activities ◽  
Core Structure ◽  
Confocal Imaging ◽  
Limiting Factor ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Apoptotic Effects

ABSTRACTPolymyxins are cyclic lipopeptide antibiotics that serve as a last line of defense against Gram-negative bacterial superbugs. However, the extensive accumulation of polymyxins in renal tubular cells can lead to nephrotoxicity, which is the major dose-limiting factor in clinical use. In order to gain further insights into the mechanism of polymyxin-induced nephrotoxicity, we have rationally designed novel fluorescent polymyxin probes to examine the localization of polymyxins in rat renal tubular (NRK-52E) cells. Our design strategy focused on incorporating a dansyl fluorophore at the hydrophobic centers of the polymyxin core structure. To this end, four novel regioselectively labeled monodansylated polymyxin B probes (MIPS-9541, MIPS-9542, MIPS-9543, and MIPS-9544) were designed, synthesized, and screened for their antimicrobial activities and apoptotic effects against rat kidney proximal tubular cells. On the basis of the assessment of antimicrobial activities, cellular uptake, and apoptotic effects on renal tubular cells, incorporation of a dansyl fluorophore at either position 6 or 7 (MIPS-9543 and MIPS-9544, respectively) of the polymyxin core structure appears to be an appropriate strategy for generating representative fluorescent polymyxin probes to be utilized in intracellular imaging and mechanistic studies. Furthermore, confocal imaging experiments utilizing these probes showed evidence of partial colocalization of the polymyxins with both the endoplasmic reticulum and mitochondria in rat renal tubular cells. Our results highlight the value of these new fluorescent polymyxin probes and provide further insights into the mechanism of polymyxin-induced nephrotoxicity.

scholarly journals Contribution of Mitochondrial Ion Channels to Chemo-Resistance in Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 761 ◽  
Author(s):  
Roberta Peruzzo ◽  
Ildiko Szabo
Keyword(s):  
Ion Channels ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
Point Of No Return ◽  
Different Types ◽  
Subsequent Activation ◽  
Induced Apoptosis ◽  
Potential Efficiency

Mitochondrial ion channels are emerging oncological targets, as modulation of these ion-transporting proteins may impact on mitochondrial membrane potential, efficiency of oxidative phosphorylation and reactive oxygen production. In turn, these factors affect the release of cytochrome c, which is the point of no return during mitochondrial apoptosis. Many of the currently used chemotherapeutics induce programmed cell death causing damage to DNA and subsequent activation of p53-dependent pathways that finally leads to cytochrome c release from the mitochondrial inter-membrane space. The view is emerging, as summarized in the present review, that ion channels located in this organelle may account in several cases for the resistance that cancer cells can develop against classical chemotherapeutics, by preventing drug-induced apoptosis. Thus, pharmacological modulation of these channel activities might be beneficial to fight chemo-resistance of different types of cancer cells.

scholarly journals Sirt5 Attenuates Cisplatin-Induced Acute Kidney Injury through Regulation of Nrf2/HO-1 and Bcl-2

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Wei Li ◽  
Yuanyuan Yang ◽  
You Li ◽  
Yueyue Zhao ◽  
Hong Jiang
Keyword(s):  
Acute Kidney Injury ◽  
Cytochrome C ◽  
Kidney Injury ◽  
Human Kidney ◽  
Dependent Manner ◽  
Cytochrome C Release ◽  
Bax Protein ◽  
Intracellular Ros ◽  
Induced Apoptosis ◽  
Mitotracker Red

Cisplatin- (CDDP) induced acute kidney injury (AKI) limits the clinical use of cisplatin. Several sirtuin (SIRT) family proteins are involved in AKI, while the roles of Sirt5 in cisplatin-induced AKI remain unknown. In the present study, we characterized the role and mechanism of Sirt5 in cisplatin-induced apoptosis using the human kidney 2 (HK-2) cell line. CDDP treatment decreased Sirt5 expression of HK-2 cells in a dose-dependent manner. In addition, Sirt5 overexpression enhanced the metabolic activity in CDDP-treated HK-2 cells while Sirt5 siRNA attenuated it. Forced expression of Sirt5 inhibited CDDP-induced apoptosis while Sirt5 siRNA showed the opposite effects. Accordingly, Sirt5 overexpression inhibited the level of caspase 3 cleavage and cytochrome c levels. Furthermore, we found that Sirt5 increased mitochondrial membrane potentials and ameliorated intracellular ROS production. Mitotracker Red staining indicated that Sirt5 overexpression was able to maintain the mitochondrial density during CDDP treatment. We also investigated possible downstream targets of Sirt5 and found that Sirt5 increased Nrf2, HO-1, and Bcl-2 while it decreased Bax protein expression. Sirt5 siRNA showed the opposite effect on these proteins. The levels of Nrf2, HO-1, and Bcl-2 proteins in HK-2 cells were also decreased after CDDP treatment. Moreover, Nrf2 and Bcl-2 siRNA partly abolished the protecting effect of Sirt5 on CDDP-induced apoptosis and cytochrome c release. Catalase inhibitor 3-AT also abolished the cytoprotective effect of Sirt5. Together, the results demonstrated that Sirt5 attenuated cisplatin-induced apoptosis and mitochondrial injury in human kidney HK-2 cells, possibly through the regulation of Nrf2/HO-1 and Bcl-2.

Nitric Oxide–Induced Apoptosis in Human Leukemic Lines Requires Mitochondrial Lipid Degradation and Cytochrome C Release

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2342-2352 ◽  
Author(s):  
Alexey Ushmorov ◽  
Frank Ratter ◽  
Volker Lehmann ◽  
Wulf Dröge ◽  
Volker Schirrmacher ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cytochrome C ◽  
Mitochondrial Protein ◽  
Jurkat Cells ◽  
Leukemic Cells ◽  
Human Leukemia ◽  
Cytochrome C Release ◽  
Mitochondrial Functions ◽  
Mitochondrial Lipid ◽  
Induced Apoptosis

Abstract We have previously shown that nitric oxide (NO) stimulates apoptosis in different human neoplastic lymphoid cell lines through activation of caspases not only via CD95/CD95L interaction, but also independently of such death receptors. Here we investigated mitochondria-dependent mechanisms of NO-induced apoptosis in Jurkat leukemic cells. NO donor glycerol trinitrate (at the concentration, which induces apoptotic cell death) caused (1) a significant decrease in the concentration of cardiolipin, a major mitochondrial lipid; (2) a downregulation in respiratory chain complex activities; (3) a release of the mitochondrial protein cytochrome c into the cytosol; and (4) an activation of caspase-9 and caspase-3. These changes were accompanied by an increase in the number of cells with low mitochondrial transmembrane potential and with a high level of reactive oxygen species production. Higher resistance of the CD95-resistant Jurkat subclone (APO-R) cells to NO-mediated apoptosis correlated with the absence of cytochrome c release and with less alterations in other mitochondrial parameters. An inhibitor of lipid peroxidation, trolox, significantly suppressed NO-mediated apoptosis in APO-S Jurkat cells, whereas bongkrekic acid (BA), which blocks mitochondrial permeability transition, provided only a moderate antiapoptotic effect. Transfection of Jurkat cells with bcl-2 led to a complete block of apoptosis due to the prevention of changes in mitochondrial functions. We suggest that the mitochondrial damage (in particular, cardiolipin degradation and cytochrome c release) induced by NO in human leukemia cells plays a crucial role in the subsequent activation of caspase and apoptosis.

scholarly journals Sensitization to CD95 ligand-induced apoptosis in human glioma cells by hyperthermia involves enhanced cytochrome c release

Oncogene ◽  
2000 ◽  
Vol 19 (19) ◽  
pp. 2338-2345 ◽  
Author(s):  
Mirjam Hermisson ◽  
Bettina Wagenknecht ◽  
Hartwig Wolburg ◽  
Tamara Glaser ◽  
Johannes Dichgans ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Glioma Cells ◽  
Human Glioma ◽  
Human Glioma Cells ◽  
Cytochrome C Release ◽  
Cd95 Ligand ◽  
Induced Apoptosis

Mcl-1 is downregulated in cisplatin-induced apoptosis, and proteasome inhibitors restore Mcl-1 and promote survival in renal tubular epithelial cells

2007 ◽  
Vol 292 (6) ◽  
pp. F1710-F1717 ◽  
Author(s):  
Cheng Yang ◽  
Varsha Kaushal ◽  
Sudhir V. Shah ◽  
Gur P. Kaushal
Keyword(s):  
Epithelial Cells ◽  
Cytochrome C ◽  
Caspase 3 ◽  
Proteasome Inhibitors ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Induced Apoptosis

Mcl-1 is an antiapoptotic member of the Bcl-2 family that plays an important role in cell survival. We demonstrate that proteasome-dependent regulation of Mcl-1 plays a critical role in renal tubular epithelial cell injury from cisplatin. Protein levels of Mcl-1 rapidly declined in a time-dependent manner following cisplatin treatment of LLC-PK1cells. However, mRNA levels of Mcl-1 were not altered following cisplatin treatment. Expression of other antiapoptotic members of the Bcl-2 family such as Bcl-2 and BclxL was not affected by cisplatin treatment. Cisplatin-induced loss of Mcl-1 occurs at the same time as the mitochondrial release of cytochrome c, activation of caspase-3, and initiation of apoptosis. Treatment of cells with cycloheximide, a protein synthesis inhibitor, revealed rapid turnover of Mcl-1. In addition, treatment with cycloheximide in the presence or absence of cisplatin demonstrated that cisplatin-induced loss of Mcl-1 results from posttranslational degradation rather than transcriptional inhibition. Overexpression of Mcl-1 protected cells from cisplatin-induced caspase-3 activation and apoptosis. Preincubating cells with the proteasome inhibitor MG-132 or lactacystin not only restored cisplatin-induced loss of Mcl-1 but also resulted in an accumulation of Mcl-1 that exceeded basal levels; however, Bcl-2 and BclxL levels did not change in response to MG-132 or lactacystin. The proteasome inhibitors effectively blocked cisplatin-induced mitochondrial release of cytochrome c, caspase-3 activation, and apoptosis. These studies suggest that proteasome regulation of Mcl-1 is crucial in the cisplatin-induced apoptosis via the mitochondrial apoptotic pathway and that Mcl-1 is an important therapeutic target in cisplatin injury to renal tubular epithelial cells.

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