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 ren al disease is still being appreciated. To further address the role of this mediator system, we evaluated the influence of absolute deficienc y of C3 and C4 on acute nephrotoxic serum nephritis (NSN). Methods. Se lective 'knockout' of C3 and C4 was routinely confirmed in null mice b y ELISA. NSN was induced by intravenous injection of a sheep anti-rat nephrotoxic serum that cross-reacts with murine glomerular antigens. D eposition of heterologous immuno globulin in wild-type glomeruli was a ssociated with rapid complement deposition and neutrophil infiltra tio n, 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 aff orded only partial protection against proteinuria. NSN was studied fur ther in C4 null mice to probe the relative roles of the classical and alternate pathway in disease pathophysiology. C3 and C4 deficiency wer e associated with equivalent inhibition of PMN recruit; ment and prote inuria. Conclusions. In aggregate, the data support a major role for c omplement in PMN recruitment in this model and point to complement-ind ependent mechanisms of proteinuria in antibody-mediated glomerulonephr itis. These 'knockout' mice should prove valuable for defining the com plement-activated mediator systems that regulate leukocyte recruitment and tissue injury in renal diseases.