Apoptosis and necrosis: Mechanisms of cell death induced by cyclosporine A in a renal proximal tubular cell line

Healy, Edel; Dempsey, Mark; Lally, Christine; Ryan, Michael P.

doi:10.1046/j.1523-1755.1998.00202.x

Cited by 153 publications

(117 citation statements)

References 37 publications

(30 reference statements)

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“…In this situation, cells (10 6 ?mL -1 ) were evaluated for size and granularity (forward and side scatter) using FACScan. The population of apoptotic cells was characterised by their smaller size, implying apoptotic shrinkage, as well as their higher granularity, representing apoptotic cytoplasmic condensation, as previously reported [15,16].…”

supporting

confidence: 69%

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Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis

Fridlender¹,

Cohen²,

Golan³

et al. 2007

Eur Respir J

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Epithelial cell injury and apoptosis are recognised as early features in idiopathic pulmonary fibrosis and bleomycin-induced fibrosis in mice. Telomerase is a known apoptosisalleviating factor. The role of telomerase was studied during bleomycin-induced lung epithelial cell (LEC) apoptosis in vitro in a mouse LEC line, and in vivo in LECs isolated from bleomycintreated mice.The current authors evaluated changes in murine telomerase reverse transcriptase (mTERT) mRNA levels and changes in telomerase activity with the TRAPeze Detection Kit, telomeric length with the TeloTTAGGG Telomere Length Kit, and LEC apoptosis with FACScan and 4,6-diamino-2-phenylindole dihydrochloride stain.There was a significant elevation in mTERT mRNA and a transient 41% increase in telomerase activity 24 h after in vitro bleomycin treatment. At 72 h, telomerase activity had fallen to 26% below levels in untreated cells. Reduction of telomerase activity over time, or by direct inhibition, significantly elevated LEC apoptosis. No change in average telomeric length was noted. In vivo, telomerase activity of LECs from bleomycin-treated mice increased at 7 and 14 days.In conclusion, telomerase activity may play a protective role against robust bleomycin-induced lung epithelial cell apoptosis. Moreover, stabilising telomerase activity may decrease epithelial cell apoptosis and the resulting lung fibrosis.

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supporting

confidence: 69%

“…Apoptosis was further evaluated using flow cytometry analysis of size and granularity as previously described [15,21]. Cells exposed to both bleomycin and telomerase inhibition had a significantly higher proportion of apoptotic cells when compared with treatment with bleomycin alone (fig.…”

Section: Telomerase In Lung Epithelial Apoptosis and Fibrosis Zg Frmentioning

confidence: 99%

Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis

Fridlender¹,

Cohen²,

Golan³

et al. 2007

Eur Respir J

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“…Engagement of death receptors, such as Fas, leads to activation of caspase-8 and subsequent apoptosis (9). In this regard, CsA increases Fas expression in cultured tubular cells, and increased FasL and Fas expression has been reported in chronic CsA nephrotoxicity (6,10). Both ligand-dependent and -independent Fas activation have been implicated in drug cytotoxicity (11,12).…”

mentioning

confidence: 96%

“…An increased rate of tubular cell apoptosis was observed in human renal biopsy specimens obtained from patients with CsA nephrotoxicity (4). In addition, several independent groups have shown that CsA induces apoptosis in tubular cells in a dose-and time-dependent manner (5)(6)(7). Apoptosis is an active mode of cell death that promotes cell loss during both acute and chronic renal damage (8).…”

mentioning

confidence: 99%

Intracellular Mechanisms of Cyclosporin A–Induced Tubular Cell Apoptosis

Justo

Lorz²,

Sanz³

et al. 2003

Journal of the American Society of Nephrology

123

115

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ABSTRACT. Tubular cell apoptosis contributes to the pathogenesis of renal injury. However, the intracellular pathways that are active in tubular epithelium are poorly understood. The lethal pathways activated by cyclosporin A (CsA), a nephrotoxin that induces caspase-dependent apoptosis in tubular epithelium, were explored. Fas expression, caspase activation, and mitochondrial injury were assessed by Western blot, flow cytometry, and microscopy in cultured murine tubular epithelial cells exposed to CsA. The influence of FasL antagonists, Bax antisense oligodeoxynucleotides, and caspase inhibitors on cell survival was explored. Tubular cells constitutively express FasL. CsA increased the expression of Fas. However, Fas had no role in CsA-induced apoptosis, as CsA did not sensitize to FasL-induced apoptosis, caspase-8 activity was not increased, and neither blocking anti-FasL antibodies nor caspase-8 inhibition prevented CsA-induced apoptosis. Apoptosis induced by CsA is associated with the translocation of Bax to the mitochondria and Bax antisense oligodeoxynucleotides protected from CsA-induced apoptosis. CsA promoted a caspase-independent release of cytochrome c and Smac/Diablo from mitochondria. CsA also led to a caspase-dependent loss of mitochondrial membrane potential. Caspase-2, caspase-3, and caspase-9 were activated, and specific caspase inhibitor prevented apoptosis and increased long-term survival. Evidence for endoplasmic reticulum stress, such as induction of GADD153, was also uncovered. However, endoplasmic reticulum-specific caspase-12 was not activated. CsA induces changes in several apoptotic pathways. However, the main lethal apoptotic pathway in CsA-exposed tubular epithelial cells involves mitochondrial injury.

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“…Cisplatin was observed to induce apoptosis at low doses, but necrosis at high doses in mouse renal epithelial cells (Lieberthal et al, 1996). This was similarly observed for cyclosporin (Healy et al, 1998). In addition, low levels of DNA damage favours p53 to induce cell-cycle arrest, as an attempt to allow cells a chance to repair the damage and survive.…”

Section: When More or Less Countsmentioning

confidence: 69%

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

2012

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Apoptosis and necrosis: Mechanisms of cell death induced by cyclosporine A in a renal proximal tubular cell line

Abstract: These results indicate that CsA is directly toxic to LLC-PK1 cells with reduced DNA synthesis and cell cycle blockade. The mode of cell death, namely apoptosis or necrosis, is dose dependent. Fas may be an important mediator of CsA induced apoptosis in renal proximal tubular cells.

Cited by 153 publications

References 37 publications

Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis

Telomerase activity in bleomycin-induced epithelial cell apoptosis and lung fibrosis

Intracellular Mechanisms of Cyclosporin A–Induced Tubular Cell Apoptosis

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

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