Heme oxygenase-1 attenuates epithelial-to-mesenchymal transition of human peritoneal mesothelial cells.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells has been regarded as an early mechanism of peritoneal fibrosis. A substantial and rapidly growing literature indicates that HO-1 provides the provenance for pathways that can interrupt virtually all major mechanisms of tissue injury. The effects of HO-1 expression on EMT, which plays a critical role in the development of peritoneal membrane (PM) fibrosis, are unknown and its roles in peritoneal fibrosis has not been studied, yet. METHODS: A piece of human omentum obtained from consenting patients undergoing elective abdominal surgery was used for study. We treated the human peritoneal mesothelial cells (HPMCs) with high glucose solution and HO-1 inducer (hemin, 10 µmol/L). To further investigate the pure effect of HO-1 on EMT of mesothelium, gene transfer of recombinant Adenovirus-harboring human HO-1 (Adv-HO-1 gene) to HPMCs was done. RESULTS: Exposure of HPMCs to HG solution resulted in an increase of the expression of mesenchymal markers such as α-smooth muscle actin (α-SMA) and was associated with a decrease in the expression of epithelial markers, E-cadherin. HO-1 protein expression was decreased in the same situation. Treatment of HPMCs with HO-1 inducer, hemin showed a dosage-dependent amelioration of HG induced changes in markers of EMT with increase of expression of HO-1. Human HO-1 gene transfection resulted in a significant increase in HO-1 expression and ameliorated HG-induced changes in expression of E-cadherin and α-SMA. CONCLUSION: Taken together, our results suggest that HO-1 has a critical role in the modulation of peritoneal fibrosis, and, more important, the suppression of EMT. This study is the first to show the beneficial effect of HO-1 on reversing EMT in MC.

Intra-peritoneal interleukin-6 system is a potent determinant of the baseline peritoneal solute transport in incident peritoneal dialysis patients.

BACKGROUND: Interleukin-6 (IL-6) is a key player in modulating inflammation. IL-6 and soluble IL-6 receptor (sIL-6R) complex induces the synthesis and secretion of various chemokines, adhesion molecules and angiogenic molecules. We hypothesized that the baseline peritoneal solute transport rate (PSTR) early after commencing peritoneal dialysis (PD) may depend largely on the IL-6/sIL-6R system. We also hypothesized that the dialysate concentrations of IL-6/sIL-6R could be closely related to local inflammation or angiogenesis in the peritoneal cavity. METHODS: Fifty incident patients with a modified peritoneal equilibration test result within 3 months after commencing PD and without a previous history of peritonitis were enrolled. Clinical parameters such as age, sex, comorbid disease, body mass index, residual renal function and C-reactive protein were assessed. Serum and dialysate markers including CA125, IL-6, sIL-6R, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) were measured and correlated with PSTR. RESULTS: Dialysate concentrations of IL-6 (r = 0.576, P < 0.001), MCP-1 (r = 0.408, P = 0.003) and Ang-2 (r = 0.408, P = 0.003) correlated with mass transfer area coefficient for creatinine (MTAC(cr)), respectively. Dialysate appearance rate (AR) of albumin correlated with dialysate concentrations of CA125 (r = 0.751, P < 0.001), IL-6 (r = 0.303, P = 0.039), sIL-6R (r = 0.497, P < 0.001), MCP-1 (r = 0.488, P < 0.001), VEGF (r = 0.443, P = 0.004) and Ang-2 (r = 0.488, P < 0.001). Neither MTAC(cr) nor AR of albumin was associated with systemic markers. Multivariate analysis showed that MTAC(cr) is independently associated with dialysate IL-6 and serum albumin. It also showed that AR of albumin is independently predicted by dialysate sIL-6R. Dialysate IL-6 correlated with dialysate concentrations of CA125 MCP-1, VEGF and Ang-2. CONCLUSION: Our study from incident PD patients suggested that (i) dialysate the IL-6 system is a potent determinant of baseline PSTR and (ii) elevation of IL-6 in the dialysate is associated with up-regulation of intra-peritoneal inflammatory and angiogenic molecules.