Saha Suppresses Peritoneal Fibrosis in Mice

Abstract

ORIGINAL ARTICLES♦ Objective: Long-term peritoneal dialysis causes peritoneal fibrosis in submesothelial areas. However, the mechanism of peritoneal fibrosis is unclear. Epigenetics is the mechanism to induce heritable changes without any changes in DNA sequences. Among epigenetic modifications, histone acetylation leads to the transcriptional activation of genes. Recent studies indicate that histone acetylation is involved in the progression of fibrosis. Therefore, we examined the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on the progression of peritoneal fibrosis in mice. ♦ Methods: Peritoneal fibrosis was induced by the injection of chlorhexidine gluconate (CG) into the peritoneal cavity of mice every other day for 3 weeks. SAHA, or a dimethylsulfoxide and saline vehicle, was administered subcutaneously every day from the start of the CG injections for 3 weeks. Morphologic peritoneal changes were assessed by Masson's trichrome staining, and fibrosis-associated factors were assessed by immunohistochemistry. ♦ Results: In CG-injected mice, a marked thickening of the submesothelial compact zone was observed. In contrast, the administration of SAHA suppressed the progression of submesothelial thickening and type III collagen accumulation in CG-injected mice. The numbers of fibroblastspecific protein-1-positive cells and α-smooth muscle actin α-positive cells were significantly decreased in the CG + SAHA group compared to that of the CG group. The level of histone acetylation was reduced in the peritoneum of the CG group, whereas it was increased in the CG + SAHA group.

Effective intraperitoneal gene transfection system using nanobubbles and ultrasound irradiation

“…Therefore, we examined transgene expression in a peritoneum surfacelabeled with DiI and cleared with the Clear T2 method because the thickness of the submesothelial layer is ca. 100 mm in a mouse model of peritoneal fibrosis (Io et al, 2015). Transgene expression in the visceral peritoneum, in the liver and stomach, was only observed on the peritoneal surface cells (Figure 6).…”

Suberoylanilide hydroxamic acid attenuates paraquat-induced pulmonary fibrosis by preventing Smad7 from deacetylation in rats

“…Histone deacetylase (HDAC) inhibition (HDACi) has been shown to suppress lung fibrosis (12)(13)(14). Suberoylanilide hydroxamic acid (SAHA, Zolinza ® , vorinostat), a FDAapproved HDACi for the treatment of cutaneous T-cell lymphoma (15), has been shown to have antifibrotic effect in both bleomycin-induced pulmonary fibrosis and chlorhexidine gluconate-induced peritoneal fibrosis in mice (16)(17)(18)(19). However, the exact molecular mechanism is unclear.…”

Role of allograft inflammatory factor‐1 in the regulation of inflammation and oxidative stress in primary peritoneal mesothelial cells

“…Peritoneal dialysis (PD) is an alternative to hemodialysis treatment for patients with end-stage kidney disease (ESKD) (Grassmann et al, 2005;Jain et al, 2012). Peritoneal fibrosis was one of the most critical complications in PD (Io et al, 2015). Some patients with peritoneal fibrosis have high mortality on account of the developing of encapsulating peritoneal sclerosis (EPS) (Io et al, 2015).…”

“…Peritoneal fibrosis was one of the most critical complications in PD (Io et al, 2015). Some patients with peritoneal fibrosis have high mortality on account of the developing of encapsulating peritoneal sclerosis (EPS) (Io et al, 2015). The most important feature of peritoneal fibrosis was that it could lead to the universal absence of a mesothelial layer in the context of submesothelial thickening (Dobbie et al, 1990;Dobbie et al, 1981;Chaimovitz, 1994).…”