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.
Nephrol Dial Transplant
; 33(4): 574-585, 2018 04 01.
Article
em En
| MEDLINE
| ID: mdl-29228352
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Osteoblastos
/
Uremia
/
Interleucina-6
/
Fator de Necrose Tumoral alfa
/
Calcificação Vascular
/
Músculo Liso Vascular
Limite:
Aged
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Nephrol Dial Transplant
Assunto da revista:
NEFROLOGIA
/
TRANSPLANTE
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Alemanha