Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling.

Abstract

BACKGROUND:

Histone deacetylase (HDAC) inhibitors are promising anti-fibrosis drugs; however, nonselective inhibition of class I and class II HDACs does not allow a detailed elucidation of the individual HDAC functions in renal fibrosis. In this study, we investigated the effect of MS-275, a selective class I HDAC inhibitor, on the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) and activation of cultured renal interstitial fibroblasts.

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.

• 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)

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

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)