Plasminogen activator inhibitor-1 and the kidney

Eddy, Allison A.

doi:10.1152/ajprenal.00032.2002

Cited by 174 publications

(145 citation statements)

References 180 publications

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“…As reported previously (37,38), HKC cells constitutively express plasminogen as well as other components of PA/plasmin axis. However, plasmin activity was found to be very low in the absence of exogenous plasminogen ( Figure 3F).…”

Section: Discussionsupporting

confidence: 73%

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Gong

Rifai²,

Tolbert³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Evidence suggests that hepatocyte growth factor (HGF) ameliorates renal fibrosis in animal models of chronic renal disease by promoting extracellular matrix catabolism. This study examined the molecular mechanisms of HGF-induced alterations in matrix degradation both in vitro and in vivo. In vitro, HGF increased the collagen catabolizing activity of human proximal tubular epithelial cells (HKC) that were treated with TGF-␤1. Increased collagen catabolism was associated with enhanced activity of both matrix metalloproteinases (MMP) and plasminogen activators (PA)/plasmin proteolytic pathways. HGF abrogated TGF-␤1-induced production of the profibrotic tissue inhibitor of metalloproteinase-2 (TIMP-2) and plasminogen activator inhibitor-1 (PAI-1). In addition, HGF induced the production of MMP-9. In vivo, continuous infusion of HGF in the rat remnant kidney model ameliorated renal fibrosis and tubulointerstitial collagen deposition. This was associated with increased tubular expression of MMP-9, enhanced in situ gelatinolytic activity, partially restored plasmin activity and decreased expression of TIMP-2 and PAI-1 in tubular cells, and upregulation of renal TIMP-3 expression. Conversely, blocking of endogenous HGF by an anti-HGF neutralizing antibody increased renal fibrosis and interstitial collagen. This was accompanied by decreased tubular expression of MMP-9, less in situ proteolytic activity, and elevated expression of TIMP-2 and PAI-1 in tubular cells. Collectively, these findings demonstrate that HGF ameliorates renal fibrosis by enhancing extracellular matrix catabolism via both MMP and the PA/plasmin proteolytic pathways.

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Section: Discussionsupporting

confidence: 73%

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Gong

Rifai²,

Tolbert³

et al. 2003

Journal of the American Society of Nephrology

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“…It plays a role in wound healing through its effects on keratinocyte cell migration (62). It is a factor promoting glomerulosclerosis and tubulointerstitial fibrosis making it an important candidate in diabetic nephropathy (63). It is necessary for peripheral nerve regeneration establishing a link to peripheral neuropathy (64).…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Activates the Plasminogen Activator Inhibitor Type 1 (PAI-1) Promoter through an AP-1 Response Element and Cooperates with Insulin for Additive Effects on PAI-1 Transcription

Vulin

Stanley

2004

Journal of Biological Chemistry

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Oxidative stress is one of the characteristics of diabetes and is thought to be responsible for many of the pathophysiological changes caused by the disease. We previously identified an insulin response element in the promoter of plasminogen activator inhibitor 1 (PAI-1) that was activated by an unidentified member of the forkhead/winged helix (Fox) family of transcription factors. This element mediated a 5-7-fold increase in PAI-1 transcription because of insulin. Here we report that oxidative stress also caused a 3-fold increase in PAI-1 transcription and that the effect was additive with that of insulin. Antioxidants prevent this response. Mutational analysis of the PAI-1 promoter revealed that oxidative stress acted at an AP-1 site at ؊60/52 of the promoter. Gel mobility shift analysis demonstrated that binding to an AP-1 oligonucleotide was increased 4-fold by oxidative stress. Jun levels were increased by oxidants as assessed by reverse transcriptase-PCR. Western blotting demonstrated that a rapid and prolonged nuclear accumulation of phospho-c-Jun followed oxidant stimulation. The nuclear c-Jun phosphorylation was not observed in cells treated with reduced glutathione. Finally, JNK/SAPK activity was found to increase in response to oxidants, and inhibition of JNK/SAP blocked TBHQ-increased PAI-1-luciferase expression. Thus, oxidative stress stimulated AP-1 and activated the PAI-1 promoter.

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“…PAI-1, a primary physiological inhibitor of plasminogen activators (uPA and tPA), inhibits both fibrinolysis and proteolysis and plays an important role in mediating the cardiovascular complications associated with T2DM such as nephropathy (10), retinopathy (11), coronary artery disorders (12), and hypertension (13). Consequently, it is believed that normalizing plasma PAI-1 levels will retard the progression of cardiovascular complications (14).…”

mentioning

confidence: 99%

Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes

Venugopal

Hanashiro

Yang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of obesity-driven type 2 diabetes mellitus and associated cardiovascular complications. Here, we show that perturbation of caveolar microdomains leads to insulin resistance and concomitant up-regulation of PAI-1 in 3T3L1 adipocytes. We present several lines of evidence showing that the phosphatidylinositol 3-kinase (PI3K) pathway negatively regulates PAI-1 gene expression. Insulin-induced PAI-1 gene expression is up-regulated by a specific inhibitor of PI3K. In addition, serum PAI-1 level is elevated in protein kinase B␣-deficient mice, whereas it is reduced in p70 ribosomal S6 kinase 1-deficient mice. The PI3K pathway phosphorylates retinoblastoma protein (pRB), known to release free E2 (adenoviral protein) factor (E2F), which we have previously demonstrated to be a transcriptional repressor of PAI-1 gene expression. Accordingly, cell-penetrating peptides that disrupt pRB-E2F interaction, and thereby release free E2F, are able to suppress PAI-1 levels that are elevated during insulin-resistant conditions. This study identifies a caveolar-dependent signal pathway that up-regulates PAI-1 in insulin-resistant adipocytes and proposes a previously undescribed pharmacological paradigm of disrupting pRB-E2F interaction to suppress PAI-1 levels. diabetes T ype 2 diabetes mellitus (T2DM) is characterized by insulin resistance, where the insulin receptor (IR) fails to elicit the metabolic signaling that is required for glucose metabolism and energy homeostasis. In insulin-sensitive tissues, the IR transduces two main signaling cascades: a metabolic signaling that is responsible for glucose uptake and glycogen synthesis and a mitogenic signaling that is responsible for cell proliferation and growth. The IR substrate (IRS)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) and Cbl-CAP-Flotillin pathways represents the major metabolic signaling, whereas the Shc-Rasextracellular regulated kinase (Erk) pathway represents the major mitogenic signaling (1). Both in animal models and clinical T2DM subjects, a selective impairment of metabolic signaling has been observed, whereas mitogenic signaling is more or less unaffected (2-4).Obesity is prominent among the plethora of factors that leads to the development of T2DM, although the molecular mechanism underlying the pathogenesis of obesity-driven T2DM is not well understood. Comparative analysis of large and small fat cells within the same fat pad reveals a 2-fold reduction in the levels of plasma membrane cholesterol in large fat cells, suggesting that a decrease in membrane cholesterol is characteristic of adipocyte hypertrophy per se (5). Recently, it has been proposed that the protein levels of caveolin-1 and -3 are inversely correlated to the body-mass index. § Plasma membrane cholesterol (6) and caveolins (7) are indispensable for the structural and functional integrity of caveolar microdomains. We therefore reasoned that obesity might lead to caveolar dysfunction. Because the IR...

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Plasminogen activator inhibitor-1 and the kidney

Cited by 174 publications

References 180 publications

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Hepatocyte Growth Factor Modulates Matrix Metalloproteinases and Plasminogen Activator/Plasmin Proteolytic Pathways in Progressive Renal Interstitial Fibrosis

Oxidative Stress Activates the Plasminogen Activator Inhibitor Type 1 (PAI-1) Promoter through an AP-1 Response Element and Cooperates with Insulin for Additive Effects on PAI-1 Transcription

Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes

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