Abstract | BACKGROUND: METHODS/FINDINGS: The UUO model was established by ligation of the left ureter and the contralateral kidney was used as a control. At seven days after UUO injury, kidney developed fibrosis as indicated by deposition of collagen fibrils and increased expression of collagen I, fibronectin and alpha-smooth muscle actin (alpha-SMA). Administration of MS-275 inhibited all these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 ( TGF-beta), increased expression of TGF-beta receptor I, and phosphorylation of Smad-3. MS-275 was also effective in suppressing phosphorylation and expression of epidermal growth factor receptor (EGFR) and its downstream signaling molecule, signal transducer and activator of transcription-3. Moreover, class I HDAC inhibition reduced the number of renal tubular cells arrested in the G2/M phase of the cell cycle, a cellular event associated with TGF-beta1overproduction. In cultured renal interstitial fibroblasts, MS-275 treatment inhibited TGF-beta induced phosphorylation of Smad-3, differentiation of renal fibroblasts to myofibroblasts and proliferation of myofibroblasts. CONCLUSIONS AND SIGNIFICANCE: These results demonstrate that class I HDACs are critically involved in renal fibrogenesis and renal fibroblast activation through modulating TGF-beta and EGFR signaling and suggest that blockade of class I HDAC may be a useful treatment for renal fibrosis.
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Authors | Na Liu, Song He, Li Ma, Murugavel Ponnusamy, Jinhua Tang, Evelyn Tolbert, George Bayliss, Ting C Zhao, Haidong Yan, Shougang Zhuang |
Journal | PloS one
(PLoS One)
Vol. 8
Issue 1
Pg. e54001
( 2013)
ISSN: 1932-6203 [Electronic] United States |
PMID | 23342059
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Acta2 protein, mouse
- Actins
- Benzamides
- Collagen Type I
- Fibronectins
- Histone Deacetylase Inhibitors
- Histones
- Pyridines
- Receptors, Transforming Growth Factor beta
- Smad3 Protein
- Transforming Growth Factor beta1
- entinostat
- ErbB Receptors
- Protein Serine-Threonine Kinases
- Receptor, Transforming Growth Factor-beta Type I
- Histone Deacetylases
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Topics |
- Acetylation
(drug effects)
- Actins
(metabolism)
- Animals
- Benzamides
(pharmacology, therapeutic use)
- Cell Cycle Checkpoints
(drug effects)
- Cell Proliferation
(drug effects)
- Collagen Type I
(metabolism)
- ErbB Receptors
(metabolism)
- Fibroblasts
(drug effects, metabolism, pathology)
- Fibronectins
(metabolism)
- Fibrosis
- Gene Expression Regulation
(drug effects)
- Histone Deacetylase Inhibitors
(pharmacology, therapeutic use)
- Histone Deacetylases
(metabolism)
- Histones
(metabolism)
- Kidney
(drug effects, metabolism, pathology)
- Leukocytes
(drug effects, immunology)
- Mice
- Phosphorylation
(drug effects)
- Protein Serine-Threonine Kinases
(metabolism)
- Pyridines
(pharmacology, therapeutic use)
- Receptor, Transforming Growth Factor-beta Type I
- Receptors, Transforming Growth Factor beta
(metabolism)
- Signal Transduction
(drug effects)
- Smad3 Protein
(metabolism)
- Transforming Growth Factor beta1
(biosynthesis, metabolism)
- Ureteral Obstruction
(drug therapy, immunology, metabolism, pathology)
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