Lipopolysaccharide-triggered acute aggravation of mesangioproliferative glomerulonephritis through activation of coagulation in a high IgA strain of ddY mice.
BACKGROUND
The high IgA (HIGA) strain of ddY mice represents an inbred model of IgA nephropathy that shows mesangioproliferative glomerulonephritis with mesangial IgA deposition. In this study, aggravation of glomerulonephritis in HIGA mice through lipopolysaccharide (LPS)-triggered activation of coagulation was investigated.


METHODS
Twelve-week-old HIGA and BALB/c mice were intraperitoneally injected with LPS twice at an interval of 3 days, and kidney specimens were collected 7 days after the second LPS injection. In an intervention experiment, the factor Xa inhibitor danaparoid was injected intraperitoneally every day for 7 days after the first LPS injection.


RESULTS
LPS injection induced macrophage infiltration and cellular proliferation in the mesangium together with fibrin deposition and monocyte chemoattractant protein 1 mRNA expression, as well as antigen deposition of tissue factor, factor V, factor X, and protease-activated receptor 2. These phenomena were obvious in HIGA mice when compared to BALB/c mice. Interestingly, toll-like receptor 4 was intensely expressed in HIGA mice before LPS injection and subsequently decreased. Danaparoid treatment significantly ameliorated proteinuria, cellular proliferation, and fibrin deposition.


CONCLUSIONS
The present data suggest that tissue factor and factor V induction by LPS may in part accelerate mesangioproliferative glomerulonephritis through activation of factor X and downstream proinflammatory and procoagulant mechanisms.
Shimosawa
Makiko
M
Division of Molecular Medicine, University of Shizuoka School of Pharmaceutical Sciences, Shizuoka General Hospital, Shizuoka 422-8526, Japan.
Sakamoto
Koji
K
Tomari
Yuki
Y
Kamikado
Kohei
K
Otsuka
Hidetaka
H
Liu
Ning
N
Kitamura
Hisayo
H
Uemura
Kazuhide
K
Nogaki
Fumiaki
F
Mori
Noriko
N
Muso
Eri
E
Yoshida
Haruyoshi
H
Ono
Takahiko
T
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000494:pharmacology; D003871:Dermatan Sulfate / Q000494:pharmacology; D005165:Factor V / Q000235:genetics / Q000378:metabolism; D005170:Factor X / Q000235:genetics / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced* / Q000276:immunology; D006497:Heparan Sulfate / Q000494:pharmacology; D007070:Immunoglobulin A / Q000378:metabolism*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D000925:Anticoagulants; D018932:Chemokine CCL2; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D005165:Factor V; D005170:Factor X; D005337:Fibrin; D006497:Heparan Sulfate; D007070:Immunoglobulin A; D008070:Lipopolysaccharides; D018809:Proliferating Cell Nuclear Antigen; D044464:Receptor, PAR-2; D013925:Thromboplastin; D051197:Toll-Like Receptor 4; C495345:TLR4 protein, human; C035838:danaparoid