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Acta Pharmacol Sin. 2014 Sep;35(9):1157-66. doi: 10.1038/aps.2014.54. Epub 2014 Aug 4.

P300-dependent STAT3 acetylation is necessary for angiotensin II-induced pro-fibrotic responses in renal tubular epithelial cells.

Author information

1
Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
2
Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
3
School of Biomedical Sciences and Institute of Vascular Medicine, Chinese University of Hong Kong, Hong Kong, China.

Abstract

AIM:

To explore the signal transducer and activator of transcription 3 (STAT3) signaling pathway, especially STAT3 acetylation, in angiotensin II (Ang II)-induced pro-fibrotic responses in renal tubular epithelial cells.

METHODS:

Rat renal tubular epithelial cell line (NRK-52E) was used. STAT3 acetylation and phosphorylation, as well as the expression of fibronectin, collagen IV and transforming growth factor-β1 (TGF-β1) were examined using Western blotting. The level and localization of STAT3 phosphorylation on Tyr705 were detected with fluorescence immunocytochemistry. The cells were transfected with a plasmid vector carrying p300 gene or siRNA targeting p300 to regulate p300 expression.

RESULTS:

Overexpression of p300 significantly increased STAT3 acetylation on Lys685, STAT3 phosphorylation on Tyr705, and the expression of TGF-β1, collagen IV and fibronectin in the cells. Treatment of the cells with Ang II (1 μmol/L) significantly increased STAT3 phosphorylation on Tyr705 through JAK2 activation, and dose-dependently increased the expression of fibronectin, collagen IV and TGF-β1. Pretreatment with curcumin, an inhibitor of JAK2 and p300, blocked Ang II-induced effects. Knockdown of p300 significantly decreased STAT3 acetylation on Lys685, and abolished Ang II-stimulated STAT3 phosphorylation on Tyr705, whereas pretreatment of the cells with C646, a selective inhibitor of p300, inhibited Ang II-induced STAT3 nuclear translocation and the expression of TGF-β1, collagen IV and fibronectin. Pretreatment of the cells with AG490, a JAK2 inhibitor, markedly inhibited Ang II-induced STAT3 phosphorylation on Tyr705 and fibronectin expression.

CONCLUSION:

p300-dependent STAT3 acetylation is necessary for Ang II-induced STAT3 phosphorylation and the consequent pro-fibrotic responses in renal tubular epithelial cells in vitro.

PMID:
25088002
PMCID:
PMC4155527
DOI:
10.1038/aps.2014.54
[Indexed for MEDLINE]
Free PMC Article

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