Imatinib

Wallace, Eric; Gewin, Leslie

doi:10.1681/asn.2012080818

Cited by 21 publications

(19 citation statements)

References 66 publications

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“…Notably, in mouse models of diabetic nephropathy (Lassila et al, 2005) and immunemediated kidney injury (Zoja et al, 2006), Imatinib has been described to reduce TGF-β1 expression in renal tissue, but the renal cell types and the molecular pathways targeted by Imatinib were not defined. In other animal models of renal fibrosis (Wang et al, 2005(Wang et al, , 2010Wallace and Gewin, 2013), Imatinib has been described to prevent TGF-β-dependent activation of fibroblasts. Interestingly, when directly delivered in vivo to proximal tubular cells in a mouse model of tubulointerstitial fibrosis, Imatinib did not show antifibrotic efficacy (Dolman et al, 2012) and this in vivo finding supports our in vitro data.…”

Section: Discussionmentioning

confidence: 99%

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Torsello

Bianchi

Meregalli

et al. 2016

Journal of Cell Science

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Renal tubular cells are involved in the tubular interstitial fibrosis observed in diabetic nephropathy. It is debated whether epithelialmesenchymal transition (EMT) affects tubular cells, which under highglucose conditions overproduce transforming growth factor-β (TGF-β), a fibrogenic cytokine involved in interstitial fibrosis development. Our study investigated the involvement of non-receptor tyrosine kinase Arg (also called Abl2) in TGF-β production. Human primary tubular cell cultures exposed to high-glucose conditions were used. These cells showed an elongated morphology, stress fibers and vimentin increment but maintained most of the epithelial marker expression and distribution. In these cells exposed to high glucose, which overexpressed and secreted active TGF-β1, Arg protein and activity was downregulated. A further TGF-β1 increase was induced by Arg silencing with siRNA, as with the Arg tyrosine kinase inhibitor Imatinib. In the cells exposed to high glucose, reactive oxygen species (ROS)-dependent Arg kinase downregulation induced both RhoA activation, through p190RhoGAPA (also known as ARHGAP35) modulation, and proteasome activity inhibition. These data evidence a new specific involvement of Arg kinase into the regulation of TGF-β1 expression in tubular cells under high-glucose conditions and provide cues for new translational approaches in diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Torsello

Bianchi

Meregalli

et al. 2016

Journal of Cell Science

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“…Besides platelet-derived growth factor receptor α/β, the nonreceptor Abelson tyrosine kinase (c-abl) [28], stem cell factor receptor c-KIT [28], macrophage colony-stimulating factor receptor (c-fms) [29] and lymphocyte-associated kinase (lck) [30] – which are all involved in development, activation, proliferation and function of immune cells – are inhibited by imatinib. In this respect, imatinib has been investigated in several models of kidney disease [31] and shown to ameliorate immunologic and fibrotic features. Furthermore, imatinib 100 mg/kg suppressed the progression and attenuated the severity of established experimental encephalomyelitis, a mouse model of multiple sclerosis [32], of autoimmune arthritis [33], and of autoimmune diabetes in mice [34].…”

Section: Discussionmentioning

confidence: 99%

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

et al. 2014

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IntroductionPulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy.MethodsThirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A “good response” was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DLCO) >15% and PaO2 > 90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved.ResultsTwenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease.ConclusionsLung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics.Trial registrationClinicalTrials.gov NCT00573326. Registered 13 December 2007.

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“…These agents have been recently used to treat autoimmune diseases, such as immune-mediated kidney injury and rheumatoid arthritis. Tyrosine kinase inhibitors (TKIs) are effective for the treatment of these diseases [31, 32]. …”

Section: Discussionmentioning

confidence: 99%

SEA Antagonizes the Imatinib-Meditated Inhibitory Effects on T Cell Activation via the TCR Signaling Pathway

Wang

Yan

Chen

et al. 2014

BioMed Research International

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The BCR-ABL kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). However, long-term imatinib treatment induces immunosuppression, which is mainly due to T cell dysfunction. Imatinib can reduce TCR-triggered T cell activation by inhibiting the phosphorylation of tyrosine kinases such as Lck, ZAP70, LAT, and PLCγ1 early in the TCR signaling pathway. The purpose of this study was to investigate whether the superantigen SEA, a potent T cell stimulator, can block the immunosuppressive effects of imatinib on T cells. Our data show that the exposure of primary human T cells and Jurkat cells to SEA for 24 h leads to the upregulation of the Lck and ZAP70 proteins in a dose-dependent manner. T cells treated with SEA prior to TCR binding had increased the tyrosine phosphorylation of Lck, ZAP70, and PLCγ1. Pretreatment with SEA prevents the inhibitory effects of imatinib on TCR signaling, which leads to T cell proliferation and IL-2 production. It is conceivable that SEA antagonizes the imatinib-mediated inhibition of T cell activation and proliferation through the TCR signaling pathway.

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Imatinib

Cited by 21 publications

References 66 publications

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study

SEA Antagonizes the Imatinib-Meditated Inhibitory Effects on T Cell Activation via the TCR Signaling Pathway

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