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Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor β
- Source :
- The FASEB Journal. 17:1-24
- Publication Year :
- 2003
- Publisher :
- Wiley, 2003.
-
Abstract
- Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Whereas PAI-1 is not expressed in normal kidneys, it is strongly induced in glomerular diseases and thus could promote the local accumulation of fibrin. To study the role of PAI-1 in the development of inflammatory glomerular injury, passive antiglomerular basement membrane (GBM) glomerulonephritis (GN) was induced in PAI-1 knockout mice and in wild-type mice of the same genetic background. Unexpectedly, PAI-1 deficiency was associated with an early and severe exacerbation of glomerular injury: Infiltration by CD4 T cells, proportion of fibrinous crescents, and renal function impairment were significantly more pronounced in PAI-1 -/- mice. Interestingly, activation of transforming growth factor (TGF)- beta, which is known to be dependent on the PA/plasmin system in vitro, was dramatically enhanced in the kidneys in the absence of PAI-1. Moreover, administration of neutralizing antibodies against TGF-beta significantly attenuated the disease in PAI-1 -/- mice. This suggests that the poor outcome of GN in PAI-1 -/- mice is consecutive to an uncontrolled activation of TGF-beta and confers PAI-1 with a new, immunomodulatory role.
- Subjects :
- medicine.medical_treatment
Kidney
Models, Biological
Biochemistry
Experimental glomerulonephritis
Mice
Plasminogen Activators
chemistry.chemical_compound
Glomerulonephritis
Thrombin
Transforming Growth Factor beta
Plasminogen Activator Inhibitor 1
Fibrinolysis
Genetics
medicine
Animals
Molecular Biology
Mice, Knockout
biology
Chemistry
Transforming growth factor beta
medicine.disease
medicine.anatomical_structure
Plasminogen activator inhibitor-1
Immunology
Cancer research
biology.protein
Plasminogen activator
Biotechnology
medicine.drug
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....a77bea344596c30c684a001e9b776ad2