Effect of cyclosporine, tacrolimus and sirolimus on cellular senescence in renal epithelial cells

Koppelstaetter, Christian; Kern, Georg; Leierer, Gisela; Mair, Stefan; Mayer, Gert; Leierer, Johannes

doi:10.1016/j.tiv.2018.01.004

Cited by 19 publications

(16 citation statements)

References 37 publications

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“…Our findings, rather, are reminiscent of partial pre-lamin A processing observed after depletion or inhibition of isoprenylcysteine carboxymethylation [24]. We cannot at present exclude that this pre-lamin A accumulation results from a senescence phenotype or cellular stress elicited by CsA [1,2,23,25]. Accumulation of pre-lamin A at the nuclear envelope however suggests that interactions of chromatin with the nuclear lamina could be altered.…”

Section: Csa Elicits Pre-lamin a Accumulationmentioning

confidence: 63%

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Forsberg

Brunet

Ali

et al. 2019

Nucleus

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Immunosuppressive drugs such as cyclosporin A (CsA) can elicit hepatotoxicity by affecting gene expression. Here, we address the link between CsA and large-scale chromatin organization in HepG2 hepatocarcinoma cells. We show the existence of lamina-associated domains (LADs) interacting with lamin A, lamin B, or both. These ‘A-B’, ‘A-only’ and ‘B-only’ LADs display distinct fates after CsA treatment: A-B LADs remain constitutive or lose A, A-only LADs mainly lose A or switch to B, and B-only LADs remain B-only or acquire A. LAD rearrangement is overall uncoupled from changes in gene expression. Three-dimensional (3D) genome modeling predicts changes in radial positioning of LADs as LADs switch identities, which are corroborated by fluorescence in situ hybridization. Our results reveal interplay between A- and B-type lamins on radial locus positioning, suggesting complementary contributions to large-scale genome architecture. The data also unveil a hitherto unsuspected impact of cytotoxic drugs on genome conformation.Abbreviations: ChIP-seq: chromatin immunoprecipitation sequencing; CsA: cyclosporin A; FISH; fluorescence in situ hybridization; ICMT: isoprenylcysteine methyltransferase; LAD: lamina-associated domain; TAD: topologically-associated domain

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Section: Csa Elicits Pre-lamin a Accumulationmentioning

confidence: 63%

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Forsberg

Brunet

Ali

et al. 2019

Nucleus

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“…Our primary focus was on recipients with available early post-transplant samples. Early was defined as within the first 100 days post-transplant, with this time point chosen to avoid confounding by the effects of post-transplant immunosuppression, which is associated with telomere attrition, and to avoid enriching the cohort for cases in which outcomes (for example, CMV viraemia) occurred before telomere length measurement [18][19][20]. Recipients with early post-transplant samples were divided into those with long (third tertile) and short (first tertile) telomeres as previously described [21,22].…”

Section: Telomere Length Measurementmentioning

confidence: 99%

Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival

et al. 2020

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Patients with short telomeres and interstitial lung disease may have decreased chronic lung allograft dysfunction (CLAD)-free survival following lung transplantation. The relationship between post-transplant telomere length and outcomes following lung transplantation has not been characterised among all recipients, regardless of native lung disease.This was a single-centre prospective cohort study. Consenting transplant recipients had their telomere length measured using quantitative real-time PCR assays on peripheral blood collected at the time of surveillance bronchoscopy. We assessed the association between early post-transplant telomere length (as measured in the first 100 days) and CLAD-free survival, time to clinically significant leukopenia, cytomegalovirus (CMV) viraemia, chronic kidney disease, and acute cellular rejection. We also assessed the association between rate of telomere shortening and CLAD-free survival.Telomere lengths were available for 98 out of 215 (45.6%) recipients who underwent lung transplant during the study period (median measurement per patient=2 (interquartile range, 1–3)). Shorter telomere length was associated with decreased CLAD-free survival (hazard ratio (HR)=1.24; 95% CI=1.03–1.48; p=0.02), leukopenia requiring granulocyte colony-stimulating factor (HR=1.17, 95% CI=1.01–1.35, p=0.03), and CMV viraemia among CMV-mismatch recipients (HR=4.04, 95% CI=1.05–15.5, p=0.04). Telomere length was not associated with acute cellular rejection or chronic kidney disease. Recipients with more rapid loss in telomere length (defined as the highest tertile of telomere shortening) did not have worse subsequent CLAD-free survival than those without rapid loss (HR=1.38, 95% CI=0.27–7.01, p=0.70).Shorter early post-transplant telomere length is associated with decreased CLAD-free survival and clinically significant leukopenia in lung transplant recipients, regardless of native lung disease.

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“…This may be particularly relevant for recipients with TERC mutations, who appear to be at higher risk for bone marrow dysfunction (19). There are also in vitro data that calcineurin inhibitors, particularly cyclosporine, may shorten telomeres more significantly than rapamycin (58,59). Although the impact of this potential accelerated shortening on bone marrow reserve is unknown, a trial of mammalian target of rapamycin inhibitors could be considered in recipients with persistent cytopenias to allow for lower doses of calcineurin inhibitors.…”

Section: Focused Reviewmentioning

confidence: 99%

Telomeres in Interstitial Lung Disease: The Short and the Long of It

Courtwright

El–Chemaly

2019

Annals ATS

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Telomeres are repetitive nucleotide sequences that cap linear chromosomes, thereby limiting progressive chromosomal shortening during cell replication. In conjunction with environmental factors, common single-nucleotide polymorphisms and rare and ultra-rare telomere-related mutations are associated with accelerated telomere shortening resulting in organ dysfunction, including interstitial lung disease (ILD). The most common telomere-related mutation-associated ILD is idiopathic pulmonary fibrosis (IPF). Up to one-third of individuals with familial IPF have shortened telomeres and/or carry a telomererelated mutation, and 1 in 10 individuals with sporadic IPF have telomere-related mutations. Regardless of ILD phenotype, individuals with short telomeres and/or known telomere-related mutations have more rapid disease progression and shorter lung transplant-free survival. Management should include initiation of antifibrotic agents for those with an IPF phenotype and early referral to a transplant center. Patients with ILD being considered for transplant should be screened for short telomeres if there is a significant family history of pulmonary fibrosis or evidence of extrapulmonary organ dysfunction associated with a short telomere syndrome. Post-transplant management of recipients with telomere-related mutations should include careful adjustment of immunosuppression regimens on the basis of bone marrow reserve. Data on the impact of shortened telomeres on post-transplant outcomes, however, remain mixed.

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Effect of cyclosporine, tacrolimus and sirolimus on cellular senescence in renal epithelial cells

Cited by 19 publications

References 37 publications

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Interplay of lamin A and lamin B LADs on the radial positioning of chromatin

Shorter telomere length following lung transplantation is associated with clinically significant leukopenia and decreased chronic lung allograft dysfunction-free survival

Telomeres in Interstitial Lung Disease: The Short and the Long of It

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