Mizoribine Suppresses the Progression of Experimental Peritoneal Fibrosis in a Rat Model

Takahashi, Shunsuke; Taniguchi, Yoshihiko; Nakashima, Ayumu; Arakawa, Tetsuji; Kawai, Tōru; Doi, Shigehiro; Ito, Takafumi; Takao, Masaki; Kohno, Nobuoki; Yorioka, Noriaki

doi:10.1159/000213896

Cited by 17 publications

(13 citation statements)

References 52 publications

(27 reference statements)

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“…During peritoneal fibrosis, the increasing amount of MyoFs may be due to the transition of peritoneal mesothelial cells, fibroblasts, mesenchymal stem cells, bone marrow cells or macrophages. Consistent with the previous study [18], a large number of α-SMA-positive cells, including MyoFs and newborn vascular endothelial cells, were found in group GLU, particularly at 5 weeks. Nevertheless, the α-SMA-positive cell numbers were greatly reduced upon intervention with rapamycin.…”

Section: Discussionsupporting

confidence: 92%

Impact of Rapamycin on Peritoneal Fibrosis and Transport Function

Xie²,

Wang³

et al. 2012

Blood Purif

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Objectives: To observe the impact of rapamycin on peritoneal fibrosis and peritoneal transport function in a rat model of peritoneal fibrosis. Methods: A total of 40 male SD rats were randomly divided into five groups, with 8 rats in each group. Group N was the normal control. In group NS, the rats were injected daily with 20 ml of saline intraperitoneally. In groups GLU, L-RAPA and H-RAPA, rats were injected daily with 20 ml of 4.25% peritoneal dialysis solution intraperitoneally, together with 150 µg of lipopolysaccharide on days 1, 3, 5 and 7. Rapamycin was administered to groups L-RAPA (250 µg/day) and H-RAPA (500 µg/day) intragastrically. On days 21 and 35, 4 rats from each group were selected to evaluate their peritoneal transport function (ultrafiltration volume, D₂/D₀ ratio). The parietal peritoneal membrane from the rats was used for pathological study. Light microscopy (HE staining and VG staining) was used to assess the morphological changes. The expression levels of Col I, α-SMA, TGF-β₁, Reca and Ki67 in the parietal peritoneal membrane were observed by immunohistochemistry. Results: The ultrafiltration volume and D₂/D₀ ratio decreased in group GLU compared with group N on day 21 (p < 0.05) and further decreased on day 35 (p < 0.01), whereas such a significant change was not observed in group L-RAPA or H-RAPA. Furthermore, severe loss of the peritoneal mesothelial cells, exposure of the collagen matrix under the mesothelial cells, and infiltration of fibroblasts and various inflammatory cells were detected in group GLU on days 21 and 35. The thickness of the submesothelial compact zone significantly increased in group GLU compared with group N (p < 0.01). However, in groups L-RAPA and H-RAPA, the morphological changes were clearly alleviated, and the submesothelial compact zone was thinner than in group GLU (p < 0.01). The expression levels of Col I, α-SMA, TGF-β₁, Ki67 and Reca in the peritoneal membrane were significantly increased in group GLU compared with group N on days 21 and 35 (p < 0.01), whereas these changes were significantly attenuated in groups L-RAPA and H-RAPA compared with group GLU (p < 0.01). Conclusions: Rapamycin had an obvious effect in inhibiting peritoneal fibrosis and improving peritoneal membrane transport function.

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Section: Discussionsupporting

confidence: 92%

Impact of Rapamycin on Peritoneal Fibrosis and Transport Function

Xie²,

Wang³

et al. 2012

Blood Purif

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“…53 The sections of collagen-1, klotho, and G9a were pretreated using heat-mediated antigen retrieval with sodium citrate buffer (pH 6) and visualized using an horse radish peroxidaseconjugated ABC system (Vector Laboratories, Burlingame, CA). The following primary antibodies were used: mouse monoclonal anti-α-SMA antibody (Sigma-Aldrich), rabbit polyclonal anti-collagen-1 antibody (Abcam, Cambridge, UK), rat polyclonal anti-klotho antibody (TransGenic), rabbit polyclonal anti-TGF-β1 antibody (Sigma-Aldrich), and rabbit polyclonal anti-G9a antibody (Abcam).…”

Section: Immunohistochemistry Of Mouse Kidney Tissuementioning

confidence: 99%

Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression

Irifuku

Doi

Sasaki

et al. 2016

Kidney International

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H3K9 methyltransferase G9a is reportedly induced by transforming growth factor-β1 (TGF-β1) and has an important role in the development of epithelial-mesenchymal transposition in cancer cells. Since the transcriptional activity of the Klotho gene is regulated by H3K9 modification, we investigated the effects of G9a on renal fibrosis and klotho expression. G9a levels were significantly upregulated by day 7 in the kidneys of unilateral ureteral-obstructed mice, but this was inhibited by TGF-β1-neutralizing antibody. Administration of G9a small interfering RNA not only decreased α-smooth muscle actin and fibronectin but also increased klotho expression in the ureteral-obstructed mice. Similarly, intraperitoneal injection of BIX01294, a specific inhibitor of G9a, showed beneficial effects on renal fibrosis and klotho expression with decreased monomethylation of H3K9 (me1). In in vitro experiments, BIX01294 also inhibited TGF-β1-induced fibrotic changes and klotho downregulation along with suppressed H3K9me1. In human kidney biopsy specimens, areas of G9a immunostaining correlated positively with H3K9me1 levels, as well as fibrotic markers, but correlated negatively with klotho expression. Thus, TGF-β1-induced G9a has an important role in the progression of renal fibrosis and reduced klotho expression through H3K9me1.

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“…[27][28][29] Recently, Tanaka et al reported MZR attenuates renal injury and intraglomerular infiltration of macrophages in patients with severe lupus nephritis. 30) It is suggested that MZR inhibits MCP-1 production by GEC and may block the infiltration of intraglomerular macrophages.…”

Section: Discussionmentioning

confidence: 99%