Crry deficiency in complement sufficient mice: C3 consumption occurs without associated renal injury

The rodent-specific complement regulator complement receptor 1-related gene/protein-y(Crry) is critical for complement homeostasis. Gene deletion is 100% embryonically lethal; Crry-deficient (Crry(-/-)) mice were rescued by back-crossing onto C3 deficiency, confirming that embryo loss was complement mediated. In order to rescue viable Crry(-/-) mice without deleting C3, we have tested inhibition of C5 during gestation. Crry(+/-) females were given neutralizing anti-C5 mAb immediately prior to mating with Crry(+/-) males and C5 inhibition maintained through pregnancy. A single, healthy Crry(-/-) female was obtained and mating with Crry(+/-) males yielded healthy litters containing equal numbers of Crry(+/-) and Crry pups. Inter-crossing Crry (/) mice yielded healthy litters of expected size. Although the mice were not anemic, exposure of Crry(-/-) erythrocytes to normal mouse serum caused C3 deposition and lysis, while transfusion into normal or C6 / mice resulted in rapid clearance. Complement activity and C3 levels in Crry(-/-) mice were markedly reduced. Comparison with factor H deficient (CfH (/)) mice revealed similar levels of residual C3; however, unlike the CfH-/- mice, Crry (/) mice showed no evidence of renal injury, demonstrating distinct roles for these regulators in protecting the kidney. (C) 2008 Published by Elsevier Ltd.