Acute nephrotoxic serum nephritis in complement knockout mice: relative roles of the classical and alternate pathways in neutrophil recruitment and proteinuria.
BACKGROUND
The importance of complement in the pathophysiology of renal disease is still being appreciated. To further address the role of this mediator system, we evaluated the influence of absolute deficiency of C3 and C4 on acute nephrotoxic serum nephritis (NSN).


METHODS
Selective 'knockout' of C3 and C4 was routinely confirmed in null mice by ELISA. NSN was induced by intravenous injection of a sheep anti-rat nephrotoxic serum that cross-reacts with murine glomerular antigens. Deposition of heterologous immunoglobulin in wild-type glomeruli was associated with rapid complement deposition and neutrophil infiltration, and followed by the development of proteinuria.


RESULTS
Neutrophil infiltration was markedly inhibited in C3-deficient mice indicating a role for complement in PMN recruitment. In contrast, C3 deficiency afforded only partial protection against proteinuria. NSN was studied further in C4 null mice to probe the relative roles of the classical and alternate pathway in disease pathophysiology. C3 and C4 deficiency were associated with equivalent inhibition of PMN recruitment and proteinuria.


CONCLUSIONS
In aggregate, the data support a major role for complement in PMN recruitment in this model and point to complement-independent mechanisms of proteinuria in antibody-mediated glomerulonephritis. These 'knockout' mice should prove valuable for defining the complement-activated mediator systems that regulate leukocyte recruitment and tissue injury in renal diseases.
Hébert
M J
MJ
Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, MA, USA.
Takano
T
T
Papayianni
A
A
Rennke
H G
HG
Minto
A
A
Salant
D J
DJ
Carroll
M C
MC
Brady
H R
HR
D000208:Acute Disease; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D003176:Complement C3 / Q000172:deficiency; D003181:Complement C4 / Q000172:deficiency; D003170:Complement Pathway, Alternative; D003171:Complement Pathway, Classical; D005921:Glomerulonephritis / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D011507:Proteinuria / Q000209:etiology*
D000936:Antigen-Antibody Complex; D003176:Complement C3; D003181:Complement C4