Glomerular complement regulation is overwhelmed in passive Heymann nephritis.
BACKGROUND
An injection of anti-Fx1A antibodies in rats leads to passive Heymann nephritis (PHN), a model of membranous nephropathy. Fx1A is a crude extract of renal cortex that contains megalin as a principal component. However, when rats are given anti-megalin antibodies, abnormal proteinuria does not occur. Because of the established complement dependence of PHN, we hypothesized that antibodies neutralizing complement regulatory proteins in the rat glomerulus also were required to induce PHN. Two likely targets are Crry and CD59, proteins abundant on the rat podocyte and contained within Fx1A that inhibit the C3 convertase and C5b-9 assembly, respectively.


METHODS
Rats were injected with anti-megalin monoclonal antibodies, followed by anti-Crry and/or anti-CD59 F(ab')(2) antibodies five days later. In a second group of experiments, rats were injected with anti-Fx1A or anti-Fx1A immunodepleted of reactivity against Crry and/or CD59.


RESULTS
In the setting of podocyte-associated anti-megalin monoclonal antibodies, simultaneous neutralization of Crry and CD59 function led to the development of significant proteinuria (11.0 +/- 2.1 mg/day, P < 0.001 vs. all other groups). In contrast, animals that had neither or only one of these complement regulators inhibited had normal urinary protein excretion (< or =6 mg/day). In animals given anti-Fx1A depleted of anti-Crry and/or anti-CD59, all groups developed typical PHN, characterized by heavy proteinuria and extensive glomerular deposition of C3 and C5b-9.


CONCLUSIONS
Crry and CD59 play an important role in restraining complement-mediated injury following subepithelial immune complex deposition; however, in PHN, their regulatory capacity is overwhelmed.
Cunningham
P N
PN
Section of Nephrology, The University of Chicago, Chicago, Illinois 60637, USA. pcunning@medicine.bsd.uchicago.edu
Hack
B K
BK
Ren
G
G
Minto
A W
AW
Morgan
B P
BP
Quigg
R J
RJ
D000818:Animals; D000954:Antigens, Surface; D018957:CD59 Antigens / Q000276:immunology; D003167:Complement Activation; D003179:Complement C3b / Q000032:analysis; D015933:Complement C3d / Q000032:analysis; D003182:Complement C5 / Q000032:analysis; D050776:Complement C5b; D005921:Glomerulonephritis / Q000276:immunology* / Q000652:urine; D026541:Heymann Nephritis Antigenic Complex; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000032:analysis; D007678:Kidney Glomerulus / Q000098:blood supply / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051381:Rats; D011956:Receptors, Cell Surface; D011951:Receptors, Complement / Q000276:immunology
D000954:Antigens, Surface; D018957:CD59 Antigens; D003182:Complement C5; C513105:Cr1l protein, rat; D026541:Heymann Nephritis Antigenic Complex; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011951:Receptors, Complement; D003179:Complement C3b; D015933:Complement C3d; D050776:Complement C5b