Cyclosporine A-induced cell cycle arrest and cell death in renal epithelial cells

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

doi:10.1046/j.1523-1755.1999.00696.x

Cited by 39 publications

(27 citation statements)

References 27 publications

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“…Because YB-1 is important in preventing premature senescence, which has been demonstrated in YB-1 knockdown mice (44), a diminished YB-1 content may cause an impaired proliferation. This is in line with the observations in renal tubular epithelial cells, in which CsA mediates cell cycle arrest (45) and enhanced senescence (46), potentially mediated by YB-1 depletion.…”

Section: Discussionsupporting

confidence: 92%

Y-Box Binding Protein-1 Mediates Profibrotic Effects of Calcineurin Inhibitors in the Kidney

Hanssen

Frye

Ostendorf

et al. 2011

The Journal of Immunology

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The immunosuppressive calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus are widely used in transplant organ recipients, but in the kidney allograft, they may cause tubulointerstitial as well as mesangial fibrosis, with TGF-β believed to be a central inductor. In this study, we report that the cold-shock protein Y-box binding protein-1 (YB-1) is a TGF-β independent downstream effector in CsA- as well as in tacrolimus- but not in rapamycin-mediated activation of rat mesangial cells (rMCs). Intracellular content of YB-1 is several-fold increased in MCs following CNI treatment in vitro and in vivo in mice. This effect ensues in a time-dependent manner, and the operative concentration range encompasses therapeutically relevant doses for CNIs. The effect of CNI on cellular YB-1 content is abrogated by specific blockade of translation, whereas retarding the transcription remains ineffective. The activation of rMCs by CNIs is accomplished by generation of reactive oxygen species. In contrast to TGF-β–triggered reactive oxygen species generation, hydrogen peroxide especially could be identified as a potent inductor of YB-1 accumulation. In line with this, hindering TGF-β did not influence CNI-induced YB-1 upregulation, whereas ERK/Akt pathways are involved in CNI-mediated YB-1 expression. CsA-induced YB-1 accumulation results in mRNA stabilization and subsequent generation of collagen. Our results provide strong evidence for a CNI-dependent induction of YB-1 in MCs that contributes to renal fibrosis via regulation of its own and collagen translation.

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Section: Discussionsupporting

confidence: 92%

Y-Box Binding Protein-1 Mediates Profibrotic Effects of Calcineurin Inhibitors in the Kidney

Hanssen

Frye

Ostendorf

et al. 2011

The Journal of Immunology

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“…Other studies with LLC-PK1 cells have shown that CsA causes a loss of cell-cell adhesion 40 as well as inducing growth arrest and cell death. 41 In the conditions of the current study, no significant loss of viability was observed. Our study proposes that within the proximal tubule, some the pathology resulting from CsA treatment might be due to a blocking of signaling by superoxide production.…”

Section: Discussionmentioning

confidence: 54%

Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

Vetter

Chen²,

Chang³

et al. 2003

Hypertension

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Abstract-Cyclosporin A (CsA) is used to reduce transplant rejection rates. Chronic use, however, has a destructive toxic effect on the kidney, resulting in hypertension. In this study, we investigated the effects of CsA treatment on the bradykinin/soluble guanylate cyclase signaling cascade and the involvement of superoxide in LLC-PK1 porcine kidney proximal tubule cells. Treatment with 1 mol/L CsA for 24 hours increased basal cGMP levels by 41%, whereas CsA inhibited bradykinin-stimulated cGMP production by 26%. Western blotting showed increased expression of eNOS, but no other protein in the bradykinin/soluble guanylate cyclase (sGC) pathway was affected. Using lucigenin-dependent chemiluminescence, we found that CsA treatment significantly increased superoxide production. Production of O 2 Ϫ was not significantly reduced by 10 mol/L oxypurinol or 30 mol/L ketoconazole. However, it was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium chloride (10 mol/L) as well as the O 2 Ϫ scavenger superoxide dismutase (SOD) (100 U). On treatment with 50 mol/L quercetin, 10 mmol/L N-acetyl-cysteine, both antioxidants, as well as the O 2 Ϫ scavenger Tiron (10 mmol/L), concomitant with 1 mol/L CsA for 24 hours the activation of cGMP production, was restored in combination with a reduction in O 2 Ϫ . Incubation with 100 mol/L menadione, a reactive oxygen generator, and 10 nmol/L bradykinin showed similar effects on the level of cGMP as with CsA. CsA treatment was found to increase nitrotyrosine levels. Key Words: cyclosporin Ⅲ bradykinin Ⅲ nitric oxide Ⅲ cyclic GMP Ⅲ antioxidants C yclosporin (CsA) is an important immunosuppressant used in improving the chances of whole organ transplant and graft survival. 1,2 However, cyclosporin treatment has been linked to several significant nephrotoxic side effects. The side effects range from afferent arteriolar constriction 3 and a reduction in glomerular filtration rate 4 to interstitial fibrosis 5 and ultimately hypertension. Although the toxic effects are well established, the exact mechanisms that lead to the pathology and hypertension are not agreed on. The proposed mechanisms for the development of hypertension focus on induction of vasoconstrictive pathways as well as obstruction of vasodilative pathways examined in patients, rat models, and endothelial cells. The pathways examined as possibly affected by CsA include the renal sensory nerve endings, 6 the renin-angiotensin system, 7 endothelin-1, 8,9 thromboxane, 9,10 and the renal kallikrein-kinin system. 11,12 Bradykinin is an important vasodilating peptide involved in the renal kallikrein-kinin system. The bradykinin peptide exerts its effects by binding to its receptor, activating a heterotrimeric G protein complex, phospholipase C, and then nitric oxide synthase (eNOS), which generates nitric oxide (NO). NO then binds to the heme group of soluble guanylate cyclase (sGC), thereby activating the enzyme to produce cGMP. 13,14 The NO synthase family and the NO radical have been shown to play an important role in many ...

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“…Injury to renal tubular epithelium is welldocumented with gene expression of apoptotic mediators such as caspases, Fas-ligand, p53 and Bax/Bcl2 ratio (8,9,(53)(54)(55) and evidence of necrotic cell death (56), however, mechanisms of cyclosporin-induced airway injury are unknown. TGFb, an important mediator of hTBEC apoptotic cell death, as well as potential link between cyclosporin and fibrosis, did not appear to be significantly elevated in cyclosporin-treated cultures compared to vehicle after 3 weeks, and although was elevated compared to day 0, more likely reflected basal apoptosis due to prolonged culture conditions.…”

Section: Discussionmentioning

confidence: 99%

“…CIs induce renal epithelial cell cycle arrest (8) and promote apoptosis (9). Cyclosporin has profibrotic effects upon renal tubule interstitium, with upregulation of transforming growth factor beta, TGFb (10).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin Inhibitor Effects on Growth and Phenotype of Human Airway Epithelial Cells In Vitro

Neuringer

Sloan

Budd

et al. 2005

American Journal of Transplantation

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Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-b stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (a and b ), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10 000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-b stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of welldifferentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.

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Cyclosporine A-induced cell cycle arrest and cell death in renal epithelial cells

Cited by 39 publications

References 27 publications

Y-Box Binding Protein-1 Mediates Profibrotic Effects of Calcineurin Inhibitors in the Kidney

Y-Box Binding Protein-1 Mediates Profibrotic Effects of Calcineurin Inhibitors in the Kidney

Cyclosporin A Disrupts Bradykinin Signaling Through Superoxide

Calcineurin Inhibitor Effects on Growth and Phenotype of Human Airway Epithelial Cells In Vitro

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