Indoxyl sulfate promotes osteogenic differentiation of vascular smooth muscle cells by miR-155-5p-dependent downregulation of matrix Gla protein via ROS/NF-κB signaling.
Exp Cell Res
; 397(1): 112301, 2020 12 01.
Article
em En
| MEDLINE
| ID: mdl-32979364
ABSTRACT
Vascular calcification (VC) is a major risk factor for increasing cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a representative uremic toxin, is closely associated with VC in CKD patients. Matrix Gla protein (MGP) plays pivotal role in VC as a calcification inhibitor. The aim of this work was to explore whether MGP was involved in IS-induced VC. Here, we demonstrated the role of MGP in the IS-induced osteogenic differentiation of human aortic smooth muscle cells (HASMCs). The methods included Von Kossa staining, immunohistochemistry, Alizarin Red staining, quantitative real-time PCR and western blotting. MGP was decreased in calcified arteries both in CKD patients and rats. In vitro, IS suppressed MGP expression in HASMCs by activating ROS/NF-κB signaling in parallel with osteogenic differentiation, which was mitigated by inhibiting ROS and NF-κB with diphenyleneiodonium and Bay11-7082. Further investigation showed that IS induced NF-κB-responsive microRNA (miR)-155-5p mediating MGP downregulation. Overexpression of miR-155-5p with mimics aggravated IS-induced MGP reduction and osteogenic differentiation. In contrast, these conditions were diminished by silencing miR-155-5p. We demonstrate that IS promotes the HASMCs phenotype switch by suppressing MGP expression via ROS/NF-κB/miR-155-5p signaling and provide a new insight for the pathogenesis of IS-induced VC.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação ao Cálcio
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Regulação da Expressão Gênica
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Proteínas da Matriz Extracelular
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NF-kappa B
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Espécies Reativas de Oxigênio
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Insuficiência Renal Crônica
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Calcificação Vascular
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Indicã
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Músculo Liso Vascular
Tipo de estudo:
Etiology_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article