The chromatin remodeling protein BRG1 mediates Ang II induced pro-fibrogenic response in renal fibroblasts.
Life Sci
; 340: 122320, 2024 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-38272440
ABSTRACT
AIMS:
Renal fibrosis is an important pathophysiological process commonly observed in patients chronic kidney disease (CKD). Angiotensin II (Ang II) is a major risk factor for CKD in part by promoting renal fibrosis. In the present study we investigated Brahma-Related Gene 1 (BRG1, encoded by Smarca4) in Ang II induced pro-fibrogenic response in renal fibroblasts. METHODS AND MATERIALS CKD was induced by chronic angiotensin II infusion. Fibroblast- and myofibroblast-specific BRG1 deletion was achieved by crossing the BRG1f/f mice to the Col1a1-CreERT2 mice and the Postn-CreERT2 mice, respectively. KEYFINDINGS:
BRG1 expression was up-regulated when fibroblasts were exposed to Ang II in vitro and in vivo. BRG1 silencing in primary renal fibroblasts blocked transition to myofibroblasts as evidenced by down-regulation of myofibroblast marker genes and reduction in cell proliferation, migration, and contraction. Consistently, deletion of BRG1 from fibroblasts or from myofibroblasts significantly attenuated renal fibrosis in mice subjected to chronic Ang II infusion. Transcriptomic analysis indicated that BRG1 primarily regulated expression of genes involved in cell migroproliferative behavior and extracellular matrix remodeling. Importantly, administration of PFI-3, a small-molecule BRG1 inhibition, markedly ameliorated Ang II induced renal fibrosis in mice.SIGNIFICANCE:
Our data support a role for BRG1 in Ang II induced fibrogenic response in renal fibroblasts and suggest that targeting BRG1 could be considered as a reasonable approach for the intervention of CKD.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Angiotensina II
/
Insuficiência Renal Crônica
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article