Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZBxNZW)F1 mice.
BACKGROUND
Lupus nephritis is characterized by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes (GBM). The latter defines end-stage disease. METHODOLOGY/PRINCIPALS: In the present study we determined the impact of antibodies to dsDNA, renal Dnase1 and matrix metalloprotease (MMP) mRNA levels and enzyme activities on early and late events in murine lupus nephritis. The major focus was to analyse if these factors were interrelated, and if changes in their expression explain basic processes accounting for lupus nephritis.


RESULTS
Early phases of nephritis were associated with chromatin-IgG complex deposition in the mesangial matrix. A striking observation was that this event correlated with appearance of anti-dsDNA antibodies and mild or clinically silent nephritis. These events preceded down-regulation of renal Dnase1. Later, renal Dnase1 mRNA level and enzyme activity were reduced, while MMP2 mRNA level and enzyme activity increased. Reduced levels of renal Dnase1 were associated in time with deficient fragmentation of chromatin from dead cells. Large fragments were retained and accumulated in GBM. Also, since chromatin fragments are prone to stimulate Toll-like receptors in e.g. dendritic cells, this may in fact explain increased expression of MMPs.


CONCLUSIONS
These scenarios may explain the basis for deposition of chromatin-IgG complexes in glomeruli in early and late stages of nephritis, loss of glomerular integrity and finally renal failure.
Fenton
Kristin
K
Department of Biochemistry, Institute of Medical Biology, Medical Faculty, University of Tromsø, Tromsø, Norway.
Fismen
Silje
S
Hedberg
Annica
A
Seredkina
Natalya
N
Fenton
Chris
C
Mortensen
Elin Synnøve
ES
Rekvig
Ole Petter
OP
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D003850:Deoxyribonuclease I / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D050533:Glomerular Basement Membrane / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D005920:Glomerular Mesangium / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D007668:Kidney / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D008181:Lupus Nephritis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D025341:Principal Component Analysis; D011507:Proteinuria / Q000150:complications / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017186:Titrimetry
D000974:Antibodies, Antinuclear; D012333:RNA, Messenger; D003850:Deoxyribonuclease I; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse