Combined glomerular deposition of polymeric rat IgA and IgG aggravates renal inflammation.
BACKGROUND
IgA nephropathy (IgAN) is characterized by deposition in the glomerular mesangium of IgA together with C3, C5b-9, and properdin. IgG deposition as a risk factor in IgAN was recently confirmed by a long-term follow-up of patients with IgAN. We previously reported on an acute model of IgA-mediated glomerular inflammation in Wistar rats.


METHODS
To investigate the effect of the combination of IgA and IgG on glomerular injury, Wistar rats were injected with a minimum dose of rat IgG in the presence or absence of a subnephritogenic dose of polymeric rat IgA. Subsequently, glomerular complement activation, influx of inflammatory cells, proteinuria, and hematuria were assessed.


RESULTS
Administration of IgG to the rats resulted in maximal proteinuria of 20.3 +/- 12.1 mg/24 h on day 2 and an absence of overt glomerular inflammation. Administration of polymeric rat IgA antibodies to rats resulted in hematuria with a moderate mesangial complement deposition. In the combination group, however, glomerular deposition of C5b-9 was dramatically increased. This was accompanied by increased proteinuria as compared with rats receiving IgA or IgG antibody injections alone on day 7. Microhematuria occurred in rats receiving either polymeric rat IgA or IgG alone or the combination. While both rat IgG and polymeric IgA induced minor mesangial cell (MC) proliferation and MC lysis, the combination resulted in a pronounced, significant increased percentage of aneurysm formation on day 7 after injection.


CONCLUSIONS
We conclude that in this model of IgA-induced glomerulopathy, a selective, complement-dependent glomerular inflammation is induced in Wistar rats by glomerular codeposition of rat isotypic monoclonal antibodies.
van Dixhoorn
M G
MG
Department of Nephrology and Pathology, Leiden University Medical Center, The Netherlands. Dixhoorn@ch1.fgg.eur.nl
Sato
T
T
Muizert
Y
Y
van Gijlswijk-Janssen
D J
DJ
De Heer
E
E
Daha
M R
MR
D000818:Animals; D000911:Antibodies, Monoclonal; D003176:Complement C3 / Q000032:analysis / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005920:Glomerular Mesangium / Q000276:immunology / Q000473:pathology; D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000473:pathology*; D006417:Hematuria / Q000276:immunology / Q000473:pathology; D007070:Immunoglobulin A / Q000032:analysis / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D011507:Proteinuria / Q000276:immunology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D000911:Antibodies, Monoclonal; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D007070:Immunoglobulin A; D007074:Immunoglobulin G