CD59a deficiency exacerbates accelerated nephrotoxic nephritis in mice.
CD59 is a complement regulatory protein that inhibits the terminal part of the complement system, the membrane attack complex (MAC), a mediator of renal injury. Mice deficient in the Cd59a gene (mCd59a-/-) were used to investigate the role of CD59 in experimentally induced accelerated nephrotoxic nephritis, a model of immune complex-mediated glomerulonephritis. After accelerated nephrotoxic nephritis was induced by administration of sheep nephrotoxic globulin, mCd59a-/- mice and strain-matched controls on two genetic backgrounds, 129/Sv x C57BL/6 and 129/Sv, were examined. For both, mCd59a-/- mice developed significantly greater glomerular cellularity than wild-type (WT) mice at day 5 after administration. At day 10 post-administration, mCd59a-/- mice exhibited more glomerular thrombosis than WT mice (thrombosis score, 1.8 [range, 1.4 to 4.0] versus 0.8 [range, 0.2 to 1.5] quadrants thrombosed per glomerulus, respectively; P = 0.0006). In the majority of experiments, mCd59a-/- mice also had significantly more proteinuria than controls; however, there was no difference in serum creatinine or albumin. Quantitative immunofluorescence of kidney sections revealed significantly more C9 (as a marker of MAC) deposition within glomeruli of mCd59a-/- mice than WT controls (P < 0.001). There was no difference in deposition of C3 and sheep IgG between the two experimental groups. The lack of CD59a, by allowing unregulated MAC deposition, exacerbates the renal injury in this model of immune complex-mediated glomerulonephritis.
Turnberg
Daniel
D
Rheumatology Section and Department of Histopathology, Faculty of Medicine, Hammersmith Campus, Imperial College, London.
Botto
Marina
M
Warren
Joanna
J
Morgan
B Paul
BP
Walport
Mark J
MJ
Cook
H Terence
HT
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism*; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012712:Serum Globulins; D013997:Time Factors
D000936:Antigen-Antibody Complex; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D008070:Lipopolysaccharides; D012712:Serum Globulins