Activated Protein C Prevents Peritoneal Fibrosis

Patients with chronic kidney disease require dialysis (hemodialysis or peritoneal dialysis) for treatment. Peritoneal dialysis is an alternative to hemodialysis for the treatment of end-stage renal disease and is based on the use of the peritoneum as a permeable membrane where ultrafiltration and diffusion between dialysate and blood can take place across the peritoneum. Peritoneal fibrosis is one of the main complications of peritoneal dialysis and affects up to 20% of patients undergoing continuous ambulatory peritoneal fibrosis. The exact mechanism of this process has yet to be elucidated and no effective therapy for the problem has been established. APC is a natural vitamin-K dependent anticoagulant protease, which also has potent antiinflammatory activity. We hypothesized that the antiinflammatory function of APC may inhibit dialysis-mediated peritoneal fibrosis. To test this hypothesis, we generated a chlorhexidine gluconate (CG)-induced peritoneal fibrosis model by injecting CG to male C57BL/6 mice for 21 days with or without intraperitoneal administration of a low dose of recombinant APC (50 µg/kg/day bodyweight) one hour before injecting CG. At 10 and 21 days after injection, the mice were sacrificed and the parietal peritoneum and omentom were dissected for histological evaluation and for analysis of expression of inflammatory molecules. Strikingly, we discovered that APC inhibits the thickness of peritoneal fibrosis and potently inhibits the mRNA expression of TGF-b1, cytokeratins, a₂-integrin, MMP-2 and 9 and also significantly increases the mRNA expression of TIMP-2 in peritoneal tissues of the experimental animals. We also discovered that APC significantly decreases the concentration of TGF-b1 and dramatically increases the concentration of tPA in peritoneal fluids. Taken together, our findings suggest that APC may have therapeutic potential in ameliorating dialysis-mediated peritoneal fibrosis.