Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy.
BACKGROUND: 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. METHODS: 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. RESULTS: Urinary albumin excretion (UAE) in diabetic PAI-1(+/+) mice increased >threefold, but remained unchanged in PAI-1(-/-) mice. Transforming growth factor-beta ( TGF-beta) and fibronectin message and protein levels were lower in diabetic PAI-1(-/-) vs. PAI-1(+/+) mice, suggesting that PAI-1 deficiency impaired TGF-beta expression despite diabetes. Indeed, recombinant PAI-1 directly stimulated TGF-beta 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-beta function suggested that uPAR mediated the cellular effect of PAI-1. CONCLUSION: PAI-1 can regulate TGF-beta 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-beta and renal ECM production and may be a therapeutic target in diabetic nephropathy.[1]References
- Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Nicholas, S.B., Aguiniga, E., Ren, Y., Kim, J., Wong, J., Govindarajan, N., Noda, M., Wang, W., Kawano, Y., Collins, A., Hsueh, W.A. Kidney Int. (2005) [Pubmed]
Annotations and hyperlinks in this abstract are from individual authors of WikiGenes or automatically generated by the WikiGenes Data Mining Engine. The abstract is from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenesOpen Access LicencePrivacy PolicyTerms of Useapsburg
