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Thromb Haemost 2008; 100(01): 90-100
DOI: 10.1160/TH08-02-0092
Wo und Healing and Inflammation / Infection
Schattauer GmbH

Immune complex-mediated glomerulonephritis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency

Nelson E. Bruno
1   Department of Diabetes and Endocrinology
,
Yutaka Yano
1   Department of Diabetes and Endocrinology
,
Yoshiyuki Takei
3   Department of Gastroenterology and Hepatology
,
Liqiang Qin
4   Department of Immunology
,
Toshinari Suzuki
1   Department of Diabetes and Endocrinology
,
John Morser
4   Department of Immunology
7   Department of Cardiovascular Research, Berlex Biosciences, Richmond, California, USA
,
Corina N. D’Alessandro-Gabazza
2   Department of Pulmonary and CriticalCare Medicine
,
Akira Mizoguchi
6   Department of Neural Regeneration and Cell Communication, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan
,
Koji Suzuki
5   Department of Molecular Pathobiology
,
Osamu Taguchi
2   Department of Pulmonary and CriticalCare Medicine
,
Esteban C. Gabazza
4   Department of Immunology
,
Yasuhiro Sumida
1   Department of Diabetes and Endocrinology
› Author AffiliationsFinancial support: The present investigation was supported by Grants-in-Aid (nos. 18590846, 17590788) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by Grants-in-Aids from the Mie Medical Research (2006), Okasan-Kato Foundation (2007) and Suzuken Memorial (2005) Foundations, and the Mie University COE Project Fund.
Further Information

Publication History

Received: 18 February 2008

Accepted after major revision: 20 May 2008

Publication Date:
22 November 2017 (online)

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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

 

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