Summary
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 thatTAFI 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 wildtype 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.
Keywords
Knockout mouse - glomerulonephritis - coagulation - fibrin - cyto-kines - plasmin
- inflammation