Pioglitazone reduces peritoneal fibrosis via inhibition of TGF-ß, MMP-2 and MMP-9 in a model of encapsulating peritoneal sclerosis

Introduction: Peritoneal dialysis (PD) is an established renal replacement therapy modality in end-stage renal disease (ESRD) patients. Although, after long-term treatment, peritoneal fibrosis (PF) results as a serious complication in some patients, causing membrane failure. Long term and progressive fibrosis may lead to encapsulating peritoneal sclerosis (EPS), the irreversible sclerosis of both visceral and peritoneal peritoneum which is associated with the symptoms of ileus and is life threatening. It is well known that increased production of ECM and decreased production of matrix-degrading proteinases (MMPs) results with the cumulation of ECM leading to fibrosis. Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-? ligands, having central role in insulin sensitization and adipogenesis and used extensively in patients with diabetes, are involved in the inflammatory cascade and reduce inflammation and fibrosis due to their ability to down-regulate proinflammatory gene expression and inflammatory cell functions.Objective: We investigated the effects of pioglitazone on fibrosis, tissue TGF-ß, MMP-2 and MMP-9 activation in an experimental model of EPS.Method: The EPS model was induced by the injection of 0.1% CG and 15% ethanol dissolved in saline (3ml) for 14 days intraperitoneally (IP). A total of 32 female Wistar albino rats were randomized to four groups. Group 1 (n:8); the control (C) group, received 0.9% saline, group 2 (n:8); the pioglitazone (Pio) group, received pioglitazone and 0.9% saline, group 3 (n:8); the encapsulating peritoneal sclerosis group, received intraperitoneal chlorhexidine gluconate (CG), group 4 (n:8); the treatment group, received CG and pioglitazone (CG+Pio). Pioglitazone (30mg/kg) was administered daily (group Pio and CG+Pio) by gavage for 14 days.Results: In the EPS group, all rats developed parietal and visceral peritoneal inflammation and fibrosis. The treatment group (CG+Pio) showed significant reduction in parietal and visceral peritoneal inflammation and submesothelial tickness as well as fibrosis. Rats with EPS receiving Pioglitazone demonstrated a similar visceral peritoneal inflammation score with the control groups (C, Pio). pro-MMP-2 was importantly supressed by pioglitazone treatment in EPS. Pioglitazone itself (Pio) induced pro-MMP-2 supression. Both EPS and treatment groups had a significant higher MMP-2 activity than the controls. Pro-MMP-9 level in the EPS group was higher when compared with the controls (C and P). Pioglitazone treatment showed a significant pro-MMP-9 supression. When compared with controls (C, Pio), TIMP-1 level was higher in the CG group. Pioglitazone treatment significantly supressed TIMP-1 level. However the TIMP-1 activity in the treatment group was still higher than the control groups (C, Pio). The EPS model resulted with an induction of TGF-ß level and Pioglitazone treatment provided a significant reduction of TGF-ß level.Conclusion:Considering statistically significant decrease in peritoneal inflammation, submesothelial tickness as well as fibrosis, along with decreased pro-MMP-2, pro-MMP-9, TIMP-1 and TGF- ß activation in pioglitazone treated group, it seems pioglitazone, via MMP and TGF- ß inhibition, may lessen accumulation of peritoneal ECM and fibrosis to some extent in an EPS model.