Portal de Periódicos da CAPES

Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy

2005; Elsevier BV; Volume: 67; Issue: 4 Linguagem: Inglês

10.1111/j.1523-1755.2005.00207.x

1523-1755

Susanne B. Nicholas, Elsa Aguiniga, Yuelan Ren, Jason Kim, Joyce S. W. Wong, Nalini Govindarajan, Masakuni Noda, Wei Wang, Yasuko Kawano, Alan R. Collins, Willa A. Hsueh,

Lipoproteins and Cardiovascular Health

Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy.BackgroundPlasminogen activator inhibitor-1 (PAI-1) is increased in kidneys of humans and animals with diabetic nephropathy and is associated with extracellular matrix (ECM) accumulation. PAI-1 may promote ECM buildup by preventing plasmin and matrix metalloproteinase (MMP) activation. However, the importance and mechanism of PAI-1 action in the pathogenesis of diabetic nephropathy is unknown.MethodsWe investigated the effect of streptozotocin (STZ)-induced diabetes in wild-type (PAI-1+/+) mice and mice null for PAI-1 (PAI-1−/−). After 1 month of diabetes, animals were placed in metabolic cages for 24-hour urine collection. Total RNA was isolated from kidney cortex for reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis, and Western blots were quantitated from cortical protein. Primary mesangial cells were grown from Sprague-Dawley rats and used in signal transduction studies.ResultsUrinary albumin excretion (UAE) in diabetic PAI-1+/+ mice increased >threefold, but remained unchanged in PAI-1−/− mice. Transforming growth factor-β (TGF-β) and fibronectin message and protein levels were lower in diabetic PAI-1−/− vs. PAI-1+/+ mice, suggesting that PAI-1 deficiency impaired TGF-β expression despite diabetes. Indeed, recombinant PAI-1 directly stimulated TGF-β message and protein via mitogen-activated protein kinase (MAPK) signal transduction in cultured mesangial cells. Urokinase plasminogen activator (uPA) inhibited this PAI-1 action in a dose-dependent manner. The inhibitory effect of antibody to uPA receptor (uPAR) on PAI-1–induced TGF-β function suggested that uPAR mediated the cellular effect of PAI-1.ConclusionPAI-1 can regulate TGF-β expression by binding to uPAR and activating the extracellular-regulated signal kinase (ERK)/MAPK pathway. Therefore, PAI-1 contributes to diabetic nephropathy by regulating TGF-β and renal ECM production and may be a therapeutic target in diabetic nephropathy. Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Plasminogen activator inhibitor-1 (PAI-1) is increased in kidneys of humans and animals with diabetic nephropathy and is associated with extracellular matrix (ECM) accumulation. PAI-1 may promote ECM buildup by preventing plasmin and matrix metalloproteinase (MMP) activation. However, the importance and mechanism of PAI-1 action in the pathogenesis of diabetic nephropathy is unknown. We investigated the effect of streptozotocin (STZ)-induced diabetes in wild-type (PAI-1+/+) mice and mice null for PAI-1 (PAI-1−/−). After 1 month of diabetes, animals were placed in metabolic cages for 24-hour urine collection. Total RNA was isolated from kidney cortex for reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis, and Western blots were quantitated from cortical protein. Primary mesangial cells were grown from Sprague-Dawley rats and used in signal transduction studies. Urinary albumin excretion (UAE) in diabetic PAI-1+/+ mice increased >threefold, but remained unchanged in PAI-1−/− mice. Transforming growth factor-β (TGF-β) and fibronectin message and protein levels were lower in diabetic PAI-1−/− vs. PAI-1+/+ mice, suggesting that PAI-1 deficiency impaired TGF-β expression despite diabetes. Indeed, recombinant PAI-1 directly stimulated TGF-β message and protein via mitogen-activated protein kinase (MAPK) signal transduction in cultured mesangial cells. Urokinase plasminogen activator (uPA) inhibited this PAI-1 action in a dose-dependent manner. The inhibitory effect of antibody to uPA receptor (uPAR) on PAI-1–induced TGF-β function suggested that uPAR mediated the cellular effect of PAI-1. PAI-1 can regulate TGF-β expression by binding to uPAR and activating the extracellular-regulated signal kinase (ERK)/MAPK pathway. Therefore, PAI-1 contributes to diabetic nephropathy by regulating TGF-β and renal ECM production and may be a therapeutic target in diabetic nephropathy.