Calcineurin inhibitors recruit protein kinases JAK2 and JNK, TLR signaling and the UPR to activate NF-κB-mediated inflammatory responses in kidney tubular cells

González‐Guerrero, Cristian; Ocaña-Salceda, Carlos; Berzal, Sergio; Carrasco, Susana; Fernández-Fernández, Beatriz; Cannata‐Ortiz, Pablo; Egido, Jesús; Ortíz, Alberto; Ramos, Adrián M.

doi:10.1016/j.taap.2013.08.011

Cited by 44 publications

(42 citation statements)

References 57 publications

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“…HK2 and RPTEC/TERT1 cells were treated with CyA and FK506 (10 μM each) for 6 and 24 h, respectively. The dose of 10 μM (CyA 12 μg/mL, FK506 8 μg/mL) is comparable to other studies [17,[39][40][41][42][43] and was identified in dose-response experiments, where HK2 cells were treated with various concentrations of CyA and FK506 (0.1-1000 μM), and 10 μM reflects the lowest dose that yielded a statistically significant decrease in proliferation by at least 20% (Supporting Information Fig. 1).…”

Section: Cni Induces Transcription Of Complement Factors But Reduces supporting

confidence: 78%

Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

et al. 2017

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One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C-) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C-system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C-factors and downregulated SOCS-3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/-2 was required for these regulations. Following knock-down and overexpression of SOCS-3, we found that SOCS-3 inhibits ERK1/-2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component-depleted conditions. In vivo, increased ERK1/-2 phosphorylation and SOCS-3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow-up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS-3 inhibits CNI-induced ERK1/-2 signalling, thereby blunting the negative control of C-system activation.

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Section: Cni Induces Transcription Of Complement Factors But Reduces supporting

confidence: 78%

Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

et al. 2017

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“…To assess whether CNIs induce direct proinflammatory effects in endothelial cells, cultured murine endothelial cells were treated with CsA or tacrolimus under standard in vitro dose and time conditions1021 and the mRNA and protein expression of key proinflammatory cytokines and adhesion molecules were assessed by PCR and ELISA assays, respectively. Treatment with CsA and tacrolimus caused a dose-dependent upregulation of the chemokines monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 (MCP1/CCL2) and regulated on activation normal T cell expressed and secreted/chemokine (C-C motif) ligand 5 (RANTES/CCL5) gene expression at 6 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling

Rodrigues‐Díez

González‐Guerrero

Ocaña-Salceda

et al. 2016

Sci Rep

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The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the rate of allograft rejection, although their chronic use is marred by a range of side effects, among them vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4. Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4−/− mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the absence of calcineurin, although its expression was required for maximal effect through upregulation of TLR4 signaling. CNI-induced TLR4 activity increased O2−/ROS production and NF-κB-regulated synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data provide new insight into the mechanisms associated with CNI vascular inflammation.

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“…FK506 promotes death, proinflammatory response, and profibrotic responses as well as nephrotoxic responses in tubular cells by activation of protein kinases, such as the TAK1/JNK/AP-1 and TLR4/Myd88/IRAK pathways [26]. KIM-1 is a type I transmembranous protein that can be exploited as a sensitive biomarker of FK506-induced nephrotoxicity in rat proximal tubule epithelial cells [4].…”

Section: Resultsmentioning

confidence: 99%

Protective effect of Korean Red Ginseng against FK506-induced damage in LLC-PK1 cells

Lee

Kang

et al. 2017

Journal of Ginseng Research

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BackgroundCompound FK506 is an immunosuppressant agent that is frequently used to prevent rejection of solid organs upon transplant. However, nephrotoxicity due to apoptosis and inflammatory response mediated by FK506 limit its usefulness. In this study, the protective effect of Korean Red Ginseng (KRG) against FK506-induced damage in LLC-PK1 pig kidney epithelial cells was investigated.MethodsLLC-PK1 cells were exposed to FK506 with KRG and cell viability was measured. Western blotting and RT-PCR analyses evaluated protein expression of MAPKs, caspase-3, and KIM-1. TLR-4 gene expression was assessed. Caspase-3 activities were also determined. The number of apoptotic cells was measured using an image-based cytometric assay.ResultsThe reduction in LLC-PK1 cell viability by 60μM FK506 was recovered by KRG cotreatment in a dose-dependent manner. The phosphorylation of p38, p44/42 MAPKs (ERK), KIM-1, cleaved caspase-3, and TLR-4 mRNA expression was increased markedly in LLC-PK1 cells treated with 60μM FK506. However, with the exception of p-ERK, elevated levels of p-p38, KIM-1, cleaved caspase-3, and TLR-4 mRNA expression were significantly decreased after cotreatment with KRG. Activity level of caspase-3 was also attenuated by KRG cotreatment. Moreover, image-based cytometric assay showed that apoptotic cell death was increased by 60μM FK506 treatment, whereas it was decreased after cotreatment with KRG.ConclusionTaken together, these results suggest that the molecular mechanism of KRG in the FK506-induced nephrotoxicity may lead to the development of an adjuvant for the inhibition of adverse effect FK506 in the kidney.

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Calcineurin inhibitors recruit protein kinases JAK2 and JNK, TLR signaling and the UPR to activate NF-κB-mediated inflammatory responses in kidney tubular cells

Cited by 44 publications

References 57 publications

Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

Calcineurin inhibitor‐induced complement system activation via ERK1/2 signalling is inhibited by SOCS‐3 in human renal tubule cells

Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling

Protective effect of Korean Red Ginseng against FK506-induced damage in LLC-PK1 cells

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