Immune complex-mediated glomerulonephritis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency.
The activity of plasmin plays a critical role in the development of chronic glomerulonephritis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a potent inhibitor of plasmin generation. We hypothesized that TAFI is involved in the pathogenesis of glomerulonephritis because it inhibits plasmin generation. To demonstrate this hypothesis, we compared the development of immune complex-mediated glomerulonephritis in wild-type and TAFI-deficient mice. After six weeks of treatment with horse spleen apoferritin and lipoplysaccharide to induce glomerulonephritis, mice deficient in TAFI had significantly better renal function as shown by lower concentrations of albumin in urine and blood urea nitrogen compared to wild-type mice. In addition, the activity of plasmin and matrix metalloproteinases was significantly increased, and mesangial matrix expansion and the deposition of collagen and fibrin in kidney tissues were significantly decreased in TAFI-knockout mice as compared to their wild-type counterparts. Depletion of fibrinogen by batroxobin (Defibrase) treatment led to equalization of the renal function and the amount of collagen deposition in the kidneys of TAFI-knockout and wild-type mice with immune complex-mediated glomerulonephritis. Together these observations suggest that TAFI-mediated inhibition of plasmin generation plays a role in the pathogenesis of glomerulonephritis, and that it may constitute a novel molecular target for the therapy of this disease.
Bruno
Nelson E
NE
Department of Immunology, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu-city, 514-8507 Mie, Japan.
Yano
Yutaka
Y
Takei
Yoshiyuki
Y
Qin
Liqiang
L
Suzuki
Toshinari
T
Morser
John
J
D'Alessandro-Gabazza
Corina N
CN
Mizoguchi
Akira
A
Suzuki
Koji
K
Taguchi
Osamu
O
Gabazza
Esteban C
EC
Sumida
Yasuhiro
Y
D000818:Animals; D000936:Antigen-Antibody Complex; D012103:Batroxobin / Q000494:pharmacology; D025901:Carboxypeptidase B2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003176:Complement C3 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005355:Fibrosis; D005921:Glomerulonephritis / Q000097:blood / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007677:Kidney Function Tests; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013997:Time Factors
D000936:Antigen-Antibody Complex; D003176:Complement C3; D016207:Cytokines; D005343:Fibrinolytic Agents; D005337:Fibrin; D005340:Fibrinogen; D025901:Carboxypeptidase B2; D012103:Batroxobin; D005341:Fibrinolysin; D020782:Matrix Metalloproteinases