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Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis.

ABSTRACT: Peritoneal fibrosis is a major complication in peritoneal dialysis (PD) patients, which leads to dialysis discontinuation. Periostin, increased by transforming growth factor ?1 (TGF-?1) stimulation, induces the expression of extracellular matrix (ECM) genes. Aberrant periostin expression has been demonstrated to be associated with PD-related peritoneal fibrosis. Therefore, the effect of periostin inhibition by an aptamer-based inhibitor on peritoneal fibrosis was evaluated. In vitro, TGF-?1 treatment upregulated periostin, fibronectin, ?-smooth muscle actin (?-SMA), and Snail expression and reduced E-cadherin expression in human peritoneal mesothelial cells (HPMCs). Periostin small interfering RNA (siRNA) treatment ameliorated the TGF-?1-induced periostin, fibronectin, ?-SMA, and Snail expression and restored E-cadherin expression in HPMCs. Similarly, the periostin-binding DNA aptamer (PA) also attenuated fibronectin, ?-SMA, and Snail upregulation and E-cadherin downregulation in TGF-?1-stimulated HPMCs. In mice treated with PD solution for 4 weeks, the expression of periostin, fibronectin, ?-SMA, and Snail was significantly increased in the peritoneum, whereas E-cadherin expression was significantly decreased. The thickness of the submesothelial layer and the intensity of Masson's trichrome staining in the PD group were significantly increased compared to the untreated group. These changes were significantly abrogated by the intraperitoneal administration of PA. These findings suggest that PA can be a potential therapeutic strategy for peritoneal fibrosis in PD patients.

SUBMITTER: Nam BY

PROVIDER: S-EPMC5436072 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis.

Nam Bo Young BY Park Jung Tak JT Kwon Young Eun YE Lee Jung Pyo JP Jung Jong Ha JH Kim Youndong Y Kim Seonghun S Park Jimin J Um Jae Eun JE Wu Meiyan M Han Seung Hyeok SH Yoo Tae-Hyun TH Kang Shin-Wook SW

Molecular therapy. Nucleic acids 20170508

Peritoneal fibrosis is a major complication in peritoneal dialysis (PD) patients, which leads to dialysis discontinuation. Periostin, increased by transforming growth factor β1 (TGF-β1) stimulation, induces the expression of extracellular matrix (ECM) genes. Aberrant periostin expression has been demonstrated to be associated with PD-related peritoneal fibrosis. Therefore, the effect of periostin inhibition by an aptamer-based inhibitor on peritoneal fibrosis was evaluated. In vitro, TGF-β1 trea ...[more]

PMID: 28624215

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Project description:Inflammatory responses in the peritoneum contribute to peritoneal dialysis (PD)-associated peritoneal fibrosis. Results of our previous study showed that increased microsomal prostaglandin E synthase-1-mediated production of prostaglandin E2 (PGE2) contributed to peritoneal fibrosis. However, the role of its downstream receptor in the progression of peritoneal fibrosis has not been established. Here, we examined the role of PGE2 receptor 4 (EP4) in the development of peritoneal fibrosis. EP4 was significantly upregulated in peritoneal tissues of PD patients with ultrafiltration failure, along with the presence of an enhanced inflammatory response. In vitro experiments showed that exposure to high glucose concentrations enhanced EP4 expression in rat peritoneal mesothelial cells (RPMCs). High-glucose-induced expression of inflammatory cytokines (monocyte chemoattractant protein-1, tumour necrosis factor α, and interleukin 1β) was significantly reduced in RPMCs treated with ONO-AE3-208, an EP4 receptor antagonist. ONO-AE3-208 also significantly decreased the expression of extracellular matrix proteins induced by high glucose concentrations. Furthermore, ONO-AE3-208 blunted activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and phosphorylation of nuclear factor kappa B (NF-κB) (p-p65). To further investigate the functional role of EP4, ONO-AE3-208 was administrated for 4 weeks in a rat model of PD, the results of which showed that ONO-AE3-208 inhibited peritoneal fibrosis and improved peritoneal dysfunction. Additionally, inflammatory cytokines in the peritoneum of PD rats treated with ONO-AE3-208 were downregulated, in line with inhibition of the NLRP3 inflammasome and NF-κB phosphorylation. In conclusion, an EP4 antagonist reduced the development of peritoneal fibrosis, possibly by suppressing NLRP3 inflammasome- and p-p65-mediated inflammatory responses. Our findings suggest that an EP4 antagonist may be therapeutically beneficial for PD-associated peritoneal fibrosis.

Dataset Information

Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis.

Publications

Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis.

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