Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis.
Cells
; 11(17)2022 09 05.
Article
em En
| MEDLINE
| ID: mdl-36078170
ABSTRACT
The TGF-ß/Smad3 signaling pathway is an important process in the pathogenesis of kidney fibrosis. However, the molecular mechanisms are not completely elucidated. The current study examined the functional role of S100A4 in regulating TGF-ß/Smad3 signaling in fibroblast activation and kidney fibrosis development. S100A4 was upregulated in the kidney in a murine model of renal fibrosis induced by folic acid nephropathy. Further, S100A4 was predominant in the tubulointerstitial cells of the kidney. Pharmacological inhibition of S100A4 with niclosamide significantly attenuated fibroblast activation, decreased collagen content, and reduced extracellular matrix protein expression in folic acid nephropathy. Overexpression of S100A4 in cultured renal fibroblasts significantly facilitated TGF-ß1-induced activation of fibroblasts by increasing the expression of α-SMA, collagen-1 and fibronectin. In contrast, S100A4 knockdown prevented TGF-ß1-induced activation of fibroblast and transcriptional activity of Smad3. Mechanistically, S100A4 interacts with Smad3 to stabilize the Smad3/Smad4 complex and promotes their translocation to the nucleus. In conclusion, S100A4 facilitates TGF-ß signaling via interaction with Smad3 and promotes kidney fibrosis development. Manipulating S100A4 may provide a beneficial therapeutic strategy for chronic kidney disease.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Insuficiência Renal Crônica
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Fator de Crescimento Transformador beta1
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Fibroblastos
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Proteína A4 de Ligação a Cálcio da Família S100
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cells
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos