Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta.
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.
Hertig
Alexandre
A
Institut National de la Santé et de la Recherche Médicale U489, Paris, France.
Berrou
Jeannig
J
Allory
Yves
Y
Breton
Laetitia
L
Commo
Frédéric
F
Costa De Beauregard
Marie-Alyette
MA
Carmeliet
Peter
P
Rondeau
Eric
E
D000818:Animals; D005921:Glomerulonephritis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D010960:Plasminogen Activators / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D010960:Plasminogen Activators; D013917:Thrombin