Cyclosporine A induces apoptosis in murine tubular epithelial cells: Role of caspases

Ortíz, Alberto; Lorz, Corina; Catalán, Marina P.; Ortiz, A.; Coca, Santiago; Egido, Jesús

doi:10.1046/j.1523-1755.1998.06808.x

Cited by 70 publications

(60 citation statements)

References 17 publications

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“…The inhibition of CsA-induced apoptosis by the broad-spectrum caspase inhibitor zVAD and by the effector caspase inhibitor DEVD provided a functional demonstration of the involvement of caspases (5). Advances in the regulation of apoptosis have identified several potential pathways for activation of the caspase cascade (24).…”

Section: Discussionmentioning

confidence: 99%

“…Final concentration of ethanol was 0.1%, and it did not influence MCT cell apoptosis. CsA-induced apoptosis was already noted at concentrations similar to those found in the blood of patients treated with CsA (1 g/ml, 0.83 mM), and it increased with dose and time (5). To study the mechanisms of CsA-induced apoptosis, a dose (10 g/ml, 8.3 mM) that induced apoptosis in a significant percentage of cells in 24 h was chosen.…”

Section: Cellsmentioning

confidence: 99%

“…Thereafter, they were rested in serum-free medium for 24 h, and CsA or vehicle (ethanol, final concentration 0.1%) was added to subconfluent cells (5). The following caspase inhibitory peptides were used: the caspase-3 inhibitor Z-Asp(OMe)-Glu(OMe)-Val-DL-Asp(OMe)-fluoromethylketone (DEVD-fmk), the pancaspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone (zVADfmk; Bachem, Bubendorf, Switzerland), the caspase-8 inhibitor Z-IleGlu(OMe)-Thr-Asp(OMe)-fluoromethylketone (IETD-fmk), the caspase-9 inhibitor Z-Leu-Glu(OMe)-His-Asp(OMe)-fluoromethylketone (LEHD-fmk), and the irreversible caspase-2 inhibitor benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethylketone (z-VDVADfmk; Calbiochem, San Diego, CA).…”

Section: Studies Of Cell Death and Apoptosismentioning

confidence: 99%

“…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%

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Intracellular Mechanisms of Cyclosporin A–Induced Tubular Cell Apoptosis

Justo

Lorz²,

Sanz³

et al. 2003

Journal of the American Society of Nephrology

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122

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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Section: Discussionmentioning

confidence: 99%

Section: Cellsmentioning

confidence: 99%

Section: Studies Of Cell Death and Apoptosismentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Intracellular Mechanisms of Cyclosporin A–Induced Tubular Cell Apoptosis

Justo

Lorz²,

Sanz³

et al. 2003

Journal of the American Society of Nephrology

Self Cite

122

115

View full text Add to dashboard Cite

show abstract

“…By contrast, Bax-mediated mitochondrial injury and caspase activation are key events in CsA-induced apoptosis of tubular cells. 67,69,70 CsA induces Bax aggregation and translocation to mitochondria, causing permeabilization of the outer mitochondrial membrane, re-lease of cytochrome c and SMAC/DIA-BLO, and activation of caspase-9 and -3. Initiator caspase-2 is also activated and may lead to mitochondrial injury.…”

Section: Nephrotoxins Illustrate Intracellular Death Pathwaysmentioning

confidence: 99%