Mesangial cell complement receptor 1-related protein y limits complement-dependent neutrophil accumulation in immune complex glomerulonephritis

P>The absence of complement receptor 1 (CR1) related gene/protein y (Crry) leads to embryonic lethality as a result of unrestricted complement activation and concomitant neutrophil infiltration. Here we used Crry(-/-)C3(+/-) mice to investigate the role of Crry in the pathogenesis of immune complex glomerulonephritis (GN). After 3 weeks of immunization with horse spleen apoferritin, six of nine Crry(-/-) C3(+/-) mice and none of the six control C3(+/-) mice developed proliferative GN (P = 0 center dot 010). After 5 weeks of immunization, GN scores in Crry(-/-) C3(+/-) mice were 0 center dot 67 +/- 0 center dot 22 mean +/- standard error of the mean (SEM), compared with 0 center dot 32 +/- 0 center dot 16 in C3(+/-) mice. Glomerular hypercellularity was attributable to neutrophil infiltration in mice with GN (1 center dot 7 +/- 0 center dot 3/glomerulus) compared with those without GN (0 center dot 4 +/- 0 center dot 1/glomerulus) (P = 0 center dot 001). Absent staining for alpha-smooth muscle actin and proliferating cell nuclear antigen suggested that mesangial cell proliferation did not play a significant role in this model. Serum C3 levels in Crry(-/-) C3(+/-) mice were approximately 20% and 30% those of wild-type mice and C3(+/-) mice, respectively. To determine whether this acquired hypocomplementaemia was relevant to this GN model system, Crry(-/-) C3(+/-) mouse kidneys were transplanted into wild-type mice followed by immunization with apoferritin for 1 or 2 weeks. Surprisingly, none of the Crry(-/-) C3(+/-) mouse kidneys developed GN at these early time-points, indicating that increasing circulating C3 levels several-fold did not increase susceptibility to GN. Renal expression of decay-accelerating factor was not different among any of the groups studied. Thus, our data indicate that mesangial cell Crry limits complement activation and subsequent neutrophil recruitment in the setting of local immune complex deposition.