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Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor β
Author(s) -
Hertig Alexandre,
Berrou Jeannig,
Allory Yves,
Breton Lætitia,
Commo Frédéric,
De Beauregard Marie-Alyette Costa,
Carmeliet Peter,
Rondeau Eric
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0084fje
Subject(s) - plasminogen activator , plasmin , glomerulonephritis , plasminogen activator inhibitor 1 , endocrinology , medicine , urokinase , transforming growth factor beta , fibrinolysis , chemistry , transforming growth factor , immunology , kidney , biochemistry , enzyme
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 CD 4 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)‐β, 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‐β 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‐β and confers PAI‐1 with a new, immunomodulatory role.