Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis

1996 ◽  
Vol 270 (4) ◽  
pp. F700-F708 ◽  
Author(s):  
W. Lieberthal ◽  
V. Triaca ◽  
J. Levine
Keyword(s):  
Cell Death ◽  
Dna Cleavage ◽  
Primary Cultures ◽  
Cell Monolayer ◽  
Membrane Integrity ◽  
Ladder Pattern ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
High Concentrations ◽  
Induced Apoptosis

We have examined the mechanisms of cell death induced by cisplatin in primary cultures of mouse proximal tubular cells. High concentrations of cisplatin (800 microM) led to necrotic cell death over a few hours. Much lower concentrations of cisplatin (8 microM) led to apoptosis, which caused loss of the cell monolayer over several days. Necrosis was characterized by a cytosolic swelling and early loss of plasma membrane integrity. In contrast, early features of cells undergoing apoptosis included cell shrinkage and loss of attachment to the monolayers. Nuclear chromatin became condensed and fragmented in apoptosing cells. These features were absent in necrotic cells. DNA electrophoresis of cells exposed to 800 microM cisplatin yielded a "smear" pattern, due to random DNA degradation. In contrast, the DNA of apoptosing cells demonstrated a "ladder" pattern resulting from internucleosomal DNA cleavage. Antioxidants delayed cisplatin-induced apoptosis but not necrosis. Thus the mechanism of cell death induced by cisplatin is concentration dependent. Reactive oxygen species play a role in mediating apoptosis but not necrosis induced by cisplatin.

scholarly journals LincRNA-p21 Inhibits Cisplatin-Induced Apoptosis of Human Renal Proximal Tubular Epithelial Cells by Sponging miR-449a

2021 ◽  
pp. 1-7
Author(s):  
Zhen Li ◽  
Gang Hou
Keyword(s):  
Breast Cancer ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Protective Role ◽  
Tubular Epithelial Cells ◽  
Breast Cancer Patients ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular ◽  
Induced Apoptosis

<b><i>Introduction:</i></b> LincRNA-p21 is predicted to interact with miR-449a, which plays a protective role in cisplatin-induced acute kidney injury (CIA). <b><i>Objective:</i></b> This study aimed to analyze the involvement of lincRNA-p21 in breast cancer patients with CIA. <b><i>Methods:</i></b> Levels of lincRNA-p21 in plasma from CIA, triple negative breast cancer, and control groups were measured by performing RT-qPCR. The potential interaction between lincRNA-p21 and miR-449a was first predicted by RT-qPCR. The relationship between lincRNA-p21 and miR-449a was analyzed by overexpression experiment. <b><i>Results:</i></b> We found that lincRNA-p21 is downregulated in CIA. Dual luciferase activity assay showed that lincRNA-p21 and miR-449a can interact with each other, while overexpression of lincRNA-p21 and miR-449a failed to affect the expression of each other. In human renal proximal tubular epithelial cells (HRPTEpCs), cisplatin led to the upregulated miR-449a but downregulated lincRNA-p21. Interestingly, lincRNA-p21 overexpression led to reduced enhancing effects of miR-449a on the cisplatin-induced apoptosis of HRPTEpCs. <b><i>Conclusion:</i></b> Therefore, lincRNA-p21 is downregulated in CIA and may sponge miR-449a to inhibit cisplatin-induced apoptosis of HRPTEpCs.

scholarly journals TCR+CD4−CD8− (double negative) T cells protect from cisplatin-induced renal epithelial cell apoptosis and acute kidney injury

2020 ◽  
Vol 318 (6) ◽  
pp. F1500-F1512
Author(s):  
Jing Gong ◽  
Sanjeev Noel ◽  
Joshua Hsu ◽  
Errol L. Bush ◽  
Lois J. Arend ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Double Negative ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Induced Apoptosis

Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. T cell receptor+CD4−CD8− double negative (DN) T cells constitute the major T cell population in the human and mouse kidney, express programmed cell death protein (PD)-1, and protect from ischemic AKI. However, the pathophysiological roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild-type mice were treated with cisplatin (30 mg/kg) or vehicle, and the effects on kidney DN T cell numbers and function were measured. In vitro experiments evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PD-L1) in renal epithelial cells. Adoptive transfer experiments assessed the therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 h and declined by 72 h after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69, and IL-10 expression, whereas CD62L, CD44, IL-17A, interferon-γ, and TNF-α were downregulated. Cisplatin treatment decreased both PD-1 and natural killer 1.1 subsets of kidney DN T cells with a pronounced effect on the PD-1 subset. In vitro kidney DN T cell coculture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2, and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD ligand 1 was reduced in proximal tubular epithelial cells cocultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI.

scholarly journals 4-Hydroxy-2-hexenal-induced apoptosis in human renal proximal tubular epithelial cells

2011 ◽  
Vol 26 (12) ◽  
pp. 3866-3873 ◽  
Author(s):  
E. H. Bae ◽  
S. Cho ◽  
S. Y. Joo ◽  
S. K. Ma ◽  
S. H. Kim ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Renal Proximal Tubular ◽  
Induced Apoptosis

scholarly journals Evidence for Agrobacterium-Induced Apoptosis in Maize Cells

2000 ◽  
Vol 13 (6) ◽  
pp. 649-657 ◽  
Author(s):  
Geneviève Hansen
Keyword(s):  
Cell Death ◽  
Dna Cleavage ◽  
Morphological Changes ◽  
Plant Cells ◽  
Plant Tissues ◽  
Apoptotic Pathway ◽  
Dicotyledonous Plant ◽  
Apoptotic Genes ◽  
Baculovirus P35 ◽  
Induced Apoptosis

Agrobacterium spp. can genetically transform most dicotyledonous plant cells whereas many monocot species are recalcitrant to Agrobacterium-mediated transformation. One major obstacle is that co-cultivation of Agrobacterium spp. with plant tissues often results in cell death. Report here is that, in maize tissues, this process resembles apoptosis, with characteristic DNA cleavage into oligonucleosomal fragments and morphological changes. Two anti-apoptotic genes from baculovirus, p35 and iap, had the ability to prevent the onset of apoptosis triggered by Agrobacterium spp. in maize tissues. p35 is reported to act as a direct inhibitor of a certain class of proteases (caspase) whereas iap may act upstream to prevent their activation. This evidence raises the possibility that caspase-like proteases may also be involved in the apoptotic pathway in plant cells.

Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells

1998 ◽  
Vol 274 (2) ◽  
pp. F315-F327 ◽  
Author(s):  
Wilfred Lieberthal ◽  
Sarah A. Menza ◽  
Jerrold S. Levine
Keyword(s):  
Cell Death ◽  
Narrow Range ◽  
Apoptotic Cell ◽  
Primary Cultures ◽  
Atp Depletion ◽  
High Dose ◽  
Renal Growth ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Epidermal Growth

The mechanisms of cell death induced by ATP depletion were studied in primary cultures of mouse proximal tubular (MPT) cells. Graded ATP depletion, ranging in severity from ∼2 to 70% of control levels, was induced by incubating cells with either antimycin or 2-deoxyglucose, with varying concentrations of dextrose. We found that cells subjected to ATP depletion below ∼15% of control died uniformly of necrosis. In contrast, cells subjected to ATP depletion between ∼25 and 70% of control all died by apoptosis. The rapidity of cell death was proportional to the severity of reduction of cell ATP content and was independent of the mechanism of cell death. Renal growth factors, epidermal growth factor (EGF) and high-dose insulin, did not ameliorate apoptotic cell death induced by ATP depletion. We conclude that ATP depletion can cause either necrosis or apoptosis in MPT cells. Furthermore, we have identified a narrow range of ATP depletion (∼15 to 25% of control) representing a threshold that determines whether cells die by necrosis or apoptosis.

Injury-induced changes in cytosolic Ca2+ in individual rabbit proximal tubule cells

1992 ◽  
Vol 262 (4) ◽  
pp. F647-F655 ◽  
Author(s):  
M. W. Smith ◽  
P. C. Phelps ◽  
B. F. Trump
Keyword(s):  
Cell Death ◽  
Cell Injury ◽  
Fluorescent Microscopy ◽  
Tubular Epithelial Cells ◽  
Proximal Tubule Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Bleb Formation ◽  
Mitochondrial Oxidation ◽  
Induced Changes

Cell injury was studied in cultured rabbit proximal tubular epithelial cells using digital-imaging fluorescent microscopy to relate changes in cytosolic Ca2+ ([Ca2+]i) to bleb formation and cell death. Fura-2-loaded cells were treated in normal (1.37 mM) and low (less than 5 microM) extracellular Ca2+ ([Ca2+]e) with 1) inhibitors of glycolysis (iodoacetate) and/or mitochondrial oxidation (KCN), 2) thiol-modifying reagents (N-ethylmaleimide, p-chloromercuribenzene, and p-chloromercuribenzene sulfonate), and 3) Ca2+ ionophore (ionomycin). All three types of injury produced both [Ca2+]e-independent and [Ca2+]e-dependent increases in [Ca2+]i. KCN + iodoacetate +/- [Ca2+]e did not produce blebbing or death within 60-90 min. Thiol modifiers and ionomycin produced blebbing, which correlated with sustained threefold or greater elevations of [Ca2+]i and loss of viability only after [Ca2+]i had risen severalfold. Blebbing and cell death could be prevented or delayed by treatment in low [Ca2+]e. Trypsin (x0.5) caused a transient (less than 5 min) elevation in [Ca2+]i as well as increases in intracellular Ca2+ pools.

Caspase-3 Activity and Carbonyl Cyanide m-Chlorophenylhydrazone-induced Apoptosis in HL-60 cells

2001 ◽  
Vol 29 (3) ◽  
pp. 243-249 ◽  
Author(s):  
Petr Mlejnek
Keyword(s):  
Cell Death ◽  
Dna Cleavage ◽  
Caspase 3 ◽  
Chromatin Condensation ◽  
Experimental System ◽  
Apoptotic Bodies ◽  
Nucleosomal Dna ◽  
Carbonyl Cyanide ◽  
Induced Apoptosis ◽  
Fluoromethyl Ketone

The role of caspase proteases in carbonyl cyanide m-chlorophenylhydrazone (CCCP)-induced apoptosis of human promyelocytic HL-60 cells was examined. Treatment of HL-60 cells with micromolar concentrations of CCCP resulted in cell death, with typical apoptotic features such as chromatin condensation, formation of apoptotic bodies, nucleosomal fragmentation of DNA and a distinct increase in caspase-3 activity. The results, however, indicated that full caspase-3 inhibition by the selective inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethyl ketone (Z-DEVD-FMK) did not prevent cell death, nor did it affect the manifestation of apoptotic hallmarks, including apoptotic bodies formation and nucleosomal DNA fragmentation. The only distinct effect that Z-DEVD-FMK exhibited was to retard the disruption of the plasma membrane. We therefore assume that caspase-3 activity itself is not essential for the manifestation of apoptotic features mentioned above. Similarly, the pan-specific caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD-FMK) did not prevent cell death. On the contrary, Z-VAD-FMK completely prevented DNA cleavage and apoptotic body formation, but it failed to completely counteract chromatin condensation. Thus, in the presence of Z-VAD-FMK, application of CCCP concentrations that otherwise induced apoptosis, resulted in the appearance of two morphologically different groups of dead cells with intact DNA. The first group included cells with necrotic-like nuclear morphology, and therefore could be taken as being “truly” necrotic in nature, because they had intact DNA. The cells of the second group formed small single-spherical nuclei with condensed chromatin. In spite of having intact DNA, they could not be taken as “truly” necrotic cells. It is evident that in the experimental system, caspase proteases play an essential role in the formation of apoptotic bodies and in the cleavage of nucleosomal DNA, but not in the condensation of chromatin. Therefore, it is likely that the choice between cell death modalities is not solely a matter of the caspase proteases present.

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