Specific collaboration between rat membrane complement regulators Crry and CD59 protects peritoneum from damage by autologous complement activation

Abstract

The peritoneal cavity is isolated from the outside and is usually a sterile environment. Patients on peritoneal dialysis (PD) have PD fluid (PDF) infused into the peritoneal cavity. We previously showed that unregulated complement activation could contribute to the development of peritoneal inflammation in yeast peritonitis in PD therapy. In that situation, suppression of local complement activation is essential to protect the host from further injury. The membrane complement regulators (CRegs), Crry, CD55 and CD59, are expressed in the rat peritoneum, especially along the mesothelial cell layer. We investigated CRegs' functional roles in the peritoneal cavity using blocking mAb against each CReg and complement activation in different PDFs. Blockade of any single CReg did not cause spontaneous peritoneal injury in rat. Combined blockade of Crry and CD59 induced focal peritoneal tissue injury and heavy accumulation of inflammatory cells with peritoneal edema at 24 h. Deposits of C3 and C5b-9 were found on the peritoneal surface after combined blocking of Crry and CD59. Systemic complement depletion by cobra venom factor abrogated these inflammatory changes. When combined blockade of Crry and CD59 was performed with PDF of different pH and glucose concentration in rats, the peritoneal injuries were enhanced with lower pH and higher glucose concentration. These results were confirmed by in vitro experiments using primary rat mesothelial cell culture. Rat CRegs, Crry and CD59, specifically collaborate to control complement activation in rat peritoneum. During PD, impairment of CReg might contribute to the development of severe peritoneal inflammation.