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

Abstract

SummaryThe 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 = 0Á010). After 5 weeks of immunization, GN scores in Crry )/) C3 +/) mice were 0Á67 ± 0Á22 mean ± standard error of the mean (SEM), compared with 0Á32 ± 0Á16 in C3 +/) mice. Glomerular hypercellularity was attributable to neutrophil infiltration in mice with GN (1Á7 ± 0Á3/glomerulus) compared with those without GN (0Á4 ± 0Á1/glomerulus) (P = 0Á001). Absent staining for a-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.

Complement Factor H Deficiency Accelerates Development of Lupus Nephritis

“…54 Serum C3 levels, anti-dsDNA antibodies, and circulating IC levels were determined by ELISA as described previously. 11,12,67 Serum samples obtained from the survival study from 6 to 16 weeks were included.…”

Complement Regulation in Renal Disease Models

“…Crry −/− C3 +/− mice actively immunized with horse spleen apoferritin had increased development of GN relative to controls, which could be attributed to neutrophil infiltration; 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. 78 In comparable studies to examine potential roles for DAF and CD59, both DAF −/− and DAF −/− CD59 −/− mice had significantly increased glomerular C3 deposition which correlated with development of GN relative to wildtype controls. 79 There were no histological or functional disease features in CD59 −/− or wildtype mice with CSS, which is indirect evidence that C5b-9 has a limited role in this model.…”