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- Title
Tumour necrosis factor-alpha in uraemic serum promotes osteoblastic transition and calcification of vascular smooth muscle cells via extracellular signal-regulated kinases and activator protein 1/c-FOS-mediated induction of interleukin 6 expression.
- Authors
Zickler, Daniel; Luecht, Christian; Willy, Kevin; Chen, Lei; Witowski, Janusz; Girndt, Matthias; Fiedler, Roman; Storr, Markus; Kamhieh-Milz, Julian; Schoon, Janosch; Geissler, Sven; Ringdén, Olle; Schindler, Ralf; Moll, Guido; Dragun, Duska; Catar, Rusan
- Abstract
Background: Vascular calcification is enhanced in uraemic chronic haemodialysis patients, likely due to the accumulation of midsize uraemic toxins, such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Here we have assessed the impact of uraemia on vascular smooth muscle cell (VSMC) calcification and examined the role of IL-6 and TNF-α as possible mediators and, most importantly, its underlying signalling pathway in VSMCs. Methods: VSMCs were incubated with samples of uraemic serum obtained from patients treated with haemodialysis for renal failure in the Permeability Enhancement to Reduce Chronic Inflammation-I clinical trial. The VSMCs were assessed for IL-6 gene regulation and promoter activation in response to uraemic serum and TNF-α with reporter assays and electrophoretic mobility shift assay and for osteoblastic transition, cellular calcification and cell viability upon osteogenic differentiation. Results: Uraemic serum contained higher levels of TNF-α and IL-6 compared with serum from healthy individuals. Exposure of VSMCs to uraemic serum or recombinant TNF-α lead to a strong upregulation of IL-6 mRNA expression and protein secretion, which was mediated by activator protein 1 (AP-1)/c-FOS-pathway signalling. Uraemic serum induced osteoblastic transition and calcification of VSMCs could be strongly attenuated by blocking TNF-α, IL-6 or AP-1/c-FOS signalling, which was accompanied by improved cell viability. Conclusion: These results demonstrate that uraemic serum contains higher levels of uraemic toxins TNF-α and IL-6 and that uraemia promotes vascular calcification through a signalling pathway involving TNF-α, IL-6 and the AP-1/c-FOS cytokine-signalling axis. Thus treatment modalities aiming to reduce systemic TNF-α and IL-6 levels in chronic haemodialysis patients should be evaluated in future clinical trials.
- Subjects
TUMOR necrosis factors; OSTEOBLASTS; BLOOD serum analysis; VASCULAR smooth muscle; EXTRACELLULAR signal-regulated kinases; AP-1 transcription factor; GENE expression
- Publication
Nephrology Dialysis Transplantation, 2018, Vol 33, Issue 4, p574
- ISSN
0931-0509
- Publication type
Article
- DOI
10.1093/ndt/gfx316