Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta.
FASEB J
; 17(13): 1904-6, 2003 Oct.
Article
en En
| MEDLINE
| ID: mdl-12897066
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.
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Bases de datos:
MEDLINE
Asunto principal:
Factor de Crecimiento Transformador beta
/
Inhibidor 1 de Activador Plasminogénico
/
Glomerulonefritis
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
FASEB J
Asunto de la revista:
BIOLOGIA
/
FISIOLOGIA
Año:
2003
Tipo del documento:
Article
País de afiliación:
Francia