PAI-1 in diabetic nephropathy

Abstract

To the Editor: The mechanisms by which plasminogen activator inhibitor-1 (PAI-1), the main plasminogen activator inhibitor, promotes fibrosis in a number of experimental models, are still intensely debated. On the one hand, PAI-1 is supposed to inhibit extracellular matrix degradation by preventing plasmin formation. On the other hand, it has been shown to prevent transforming growth factor (TGF) beta activation and, thus, to prevent extracellular matrix production1.Hertig A. Rondeau E. Plasminogen activator inhibitor type 1: The two faces of the same coin.Curr Opin Nephrol Hypertens. 2004; 13: 39-44Crossref PubMed Scopus (14) Google Scholar. Nicholas et al recently provided experimental, in vivo data suggesting that PAI-1 deficiency might be helpful in the prevention of diabetic nephropathy: when compared to wild-type animals, PAI-1 knockout mice have, thus, a lower urinary albumin excretion and a lower synthesis of fibronectin in the kidney after streptozotocin injection2.Nicholas S.B. Aguiniga E. Ren Y. et al.Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy.Kidney Int. 2005; 67: 1297-1307Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar. Interestingly, PAI-1 is reported by these authors to enhance TGF beta synthesis by mesangial cells, a finding that is somewhat provocative because TGF beta is itself a potent enhancer of the PAI-1 promoter gene, and because recent works by Luttun et al and our group demonstrated that PAI-1 plays a critical role in the regulation of the TGF beta activation (i.e., PAI-1 inhibits TGF-beta activation)3.Luttun A. Lupu F. Storkebaum E. et al.Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice.Arterioscler Thromb Vasc Biol. 2002; 22: 499-505Crossref PubMed Scopus (105) Google Scholar,4.Hertig A. Berrou J. Allory Y. et al.Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta.FASEB J. 2003; 17: 1904-1906PubMed Google Scholar. Moreover, in Nicholas' study, the induction of TGF-beta synthesis, at the mRNA and at the protein level, in diabetic PAI-1 +/+ mice, is weak when compared with nondiabetic mice (×1.5), and is hardly distinguishable from the induction observed in PAI-1 -/- mice, at least for the eye Figure 3. Another striking result is that the level of TGF-beta expression and production by the kidney is higher in PAI-1 -/- mice than in PAI-1 +/+ mice, in either basal or diabetic conditions. In the absence of pathologic data, including measurements of the glomerular basement membrane thickness, it is therefore difficult to conclude that PAI-1 knockout animals could be protected towards diabetic nephropathy and that this would be related to a lower concentration of TGF-beta.