C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis.
We studied the role of the C5b-9 membrane attack complex in two models of inflammatory glomerulonephritis (GN) initiated by acute glomerular endothelial injury in Piebold-viral-Glaxo (PVG) complement-sufficient rats (C+), C6-deficient rats (C6-), and rats systematically depleted of complement with cobra venom factor (CVF). GN was induced by performing a left nephrectomy and selectively perfusing the right kidney with either 1) the lectin concanavalin A (Con A) followed by complement-fixing anti-Con A (Con A GN) or 2) purified complement-fixing goat anti-rat glomerular endothelial cell (GEN) antibody [immune-mediated thrombotic microangiopathy (ITM)]. Comparable levels of GEN apoptosis were detected in C+ animals in both models. CVF administration reduced GEN apoptosis by 10- to 12-fold. GEN apoptosis was C5b-9 dependent because PVG C6- rats were protected from GEN loss. Furthermore, functional inhibition of the cell surface complement regulatory protein CD59 by renal perfusion with anti-CD59 antibody in ITM resulted in a 3.5-fold increase in GEN apoptosis. Last, in Con A GN, abrogation of GEN apoptosis preserved endothelial integrity and renal function. This study demonstrates the specific role of C5b-9 in the induction of GEN apoptosis in experimental inflammatory GN, a finding with implications for diseases associated with the presence of antiendothelial cell antibodies.
Hughes
J
J
Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, 98195, USA. jeremyh@u.washington.edu
Nangaku
M
M
Alpers
C E
CE
Shankland
S J
SJ
Couser
W G
WG
Johnson
R J
RJ
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D003183:Complement C6 / Q000172:deficiency / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D003208:Concanavalin A / Q000633:toxicity; D004195:Disease Models, Animal; D004727:Endothelium / Q000276:immunology / Q000473:pathology; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008297:Male; D051381:Rats; D013927:Thrombosis / Q000276:immunology / Q000473:pathology
D003183:Complement C6; D015938:Complement Membrane Attack Complex; D003208:Concanavalin A