Nephrology Dialysis Transplantation, Vol 13, Issue 11 2799-2803, Copyright © 1998 by Oxford University Press
M Hebert, T Takano, A Papayianni, H Rennke, A Minto, D Salant, M Carroll and H Brady
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. Key
words: complement; glomerulonephritis; knockout; neutrophils;
proteinuria
ORIGINAL ARTICLES
Acute nephrotoxic serum nephritis in complement knockout mice: relative roles of the classical and alternate pathways in neutrophil recruitment and proteinuria
Renal Division, Department of Medicine, and Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, MA, USA; Renal Division, Boston University, MA, USA; Corresponding author at: Department of Medicine and Therapeutics, University College Dublin, Maer Miseracordiae Hospital, 41 Eccles Street, Dublin 7, Ireland
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