Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy

Nicholas, Susanne B.; Aguiniga, Elsa; Ren, Yi; Kim, Jason; Wong, Janus Siu Him; Govindarajan, Nalini; Noda, Masakuni; Wang, Wei; Kawano, Yasunobu; Collins, Alan R.; Hsueh, Willa A.

doi:10.1111/j.1523-1755.2005.00207.x

Cited by 141 publications

(143 citation statements)

References 51 publications

(43 reference statements)

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“…Indeed, α 2 -antiplasmin, the most abundant form in normal kidneys, was suppressed following ureteral obstruction [11] . Consistent with our results, some reports have shown that the increase in PAI-1 and fibrosis is not always accompanied by a decrease in plasmin and MMP-2 activities [11,12,14,16] . Further, PAI-1 deficiency and decreased fibrosis are not always accompanied by an augmentation of plasmin and MMP-2 activities.…”

Section: Wwwchinapharcom Liu X Et Alsupporting

confidence: 81%

“…PAI-1's profibrotic effect is presumed to be exerted by inhibiting plasmin generation. This explanation, however, has been disputed in some reports [11,12,14,16] .…”

Section: Introductionmentioning

confidence: 80%

“…Recently, attention has focused on the role of PAI-1 in the pathogenesis of fibrosis based on its increased expression in a variety of fibrotic diseases and on the beneficial effects of its inhibition or depletion in some fibrosis models [9][10][11][12][13][14][15] ; however, the mechanism of its action remains controversial. In vitro studies document that ECM degradation by cultured mesangial cells is inhibited by plasmin inhibitors and increased by the addition of a PAI-1 monoclonal antibody [19] .…”

Section: Wwwchinapharcom Liu X Et Almentioning

confidence: 99%

“…Transgenic mice overexpressing PAI-1 develop severe fibrosis in several experimental fibrosis models [8][9][10] . In contrast, PAI-1 deficiency or inhibition results in decreased fibrosis [8,[10][11][12][13][14][15][16] . These studies demonstrate a role for PAI-1 in fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Amelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin

et al. 2011

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Aim: To examine the effects of all-trans retinoic acid (atRA) on renal morphology and function as well as on renal plasminogen activator inhibitor-1 (PAI-1) expression and plasmin activity in rats with 5/6 nephrectomy. Methods: Adult male Sprague Dawley rats were given 5/6 nephrectomy or sham operation. Renal function was measured 2 weeks later. The nephrectomized rats were assigned to groups matched for proteinuria and treated with vehicle or atRA (5 or 10 mg/kg by gastric gavage once daily) for the next 12 weeks. Rats with sham operation were treated with vehicle. At the end of the treatments, kidneys were collected for histological examination, Western blot analysis, and enzymatic activity measurements. Results: The 5/6 nephrectomy promoted hypertension, renal dysfunction, and glomerulosclerosis. These changes were significantly reduced in the atRA-treated group. The expressions of PAI-1 and α-smooth muscle actin (α-SMA) were significantly increased in the vehicle-treated nephrectomized rats. Treatment with atRA significantly reduced the expressions of PAI-1 and α-SMA. However, plasmin activity remained unchanged following atRA treatment. Conclusion: Treatment with atRA ameliorates glomerulosclerosis and improves renal function in rats with 5/6 nephrectomy. This is associated with a decrease in PAI-1 and α-SMA, but not with a change in plasmin activity.

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Section: Wwwchinapharcom Liu X Et Alsupporting

confidence: 81%

“…PAI-1's profibrotic effect is presumed to be exerted by inhibiting plasmin generation. This explanation, however, has been disputed in some reports [11,12,14,16] .…”

Section: Introductionmentioning

confidence: 80%

Section: Wwwchinapharcom Liu X Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin

et al. 2011

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“…If this is the case, PAI-1 would have a rather protective role, by inhibiting in part the large amounts of t-PA released in the presence of AGEs. This seems unlikely after the recent studies that PAI-1 knock-out mice have a lower proteinuria than their wild-type controls after induction of diabetes by streptozotocin (34)(35)(36).…”

Section: Discussionmentioning

confidence: 84%

Advanced glycation end products regulate extracellular matrix protein and protease expression by human glomerular mesangial cells

Berrou

Tostivint

Verrecchia³

et al. 2009

Int J Mol Med

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Abstract. Advanced glycation end products (AGEs) may play a role in the pathogenesis of diabetic nephropathy, by modulating extracellular matrix turnover. AGEs are known to activate specific membrane receptors, including the receptor for AGE (RAGE). In the present study, we analyzed the various receptors for AGEs expressed by human mesangial cells and we studied the effects of glycated albumin and of carboxymethyl lysine on matrix protein and remodelling enzyme synthesis. Membrane RAGE expression was confirmed by FACS analysis. Microarray methods, RT-PCR, and Northern blot analysis were used to detect and confirm specific gene induction. Zymographic analysis and ELISA were used to measure the induction of tPA and PAI-1. We show herein that cultured human mesangial cells express AGE receptor type 1, type 2 and type 3 and RAGE. AGEs (200 μg/ml) induced at least a 2-fold increase in mRNA for 10 genes involved in ECM remodelling, including tPA, PAI-1 and TIMP-3. The increase in tPA synthesis was confirmed by fibrin zymography. The stimulation of PAI-1 synthesis was confirmed by ELISA. AGEs increased PAI-1 mRNA through a signalling pathway involving reactive oxygen species, the MAP kinases ERK-1/ERK-2 and the nuclear transcription factor NF-κB, but not AP-1. Carboxymethyl lysine (CML, 5 μM), which is a RAGE ligand, also stimulated PAI-1 synthesis by mesangial cells. In addition, a blocking anti-RAGE antibody partially inhibited the AGE-stimulated gene expression and decreased the PAI-1 accumulation induced by AGEs and by CML. Inhibition of AGE receptors or neutralization of the protease inhibitors TIMP-3 and PAI-1 could represent an important new therapeutic strategy for diabetic nephropathy.

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Adipose Tissue‐Derived Plasminogen Activator Inhibitor‐1 Function and Regulation

Kaji

2016

Comprehensive Physiology

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Adipose tissue has recently been reevaluated as an endocrine organ, and adipose-tissue-derived endocrine factors are termed adipokines. Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of PAs, which convert plasminogen into plasmin, a critical protease involved in fibrinolysis. PAI-1 induces fibrinogenesis by suppressing intravascular and tissue fibrinolysis. Moreover, PAI-1 exerts various cellular effects independently of fibrinolysis. Although PAI-1 is expressed in various tissues, its expression is regulated by numerous growth factors, cytokines, and hormones in a paracrine and endocrine manner. Adipocyte-derived PAI-1, predominantly expressed in visceral fat, is released into the circulation in parallel with increased fat mass, and it functions as a crucial adipokine that negatively affects physiological metabolism and vascular biology. Elevated PAI-1 levels induce insulin resistance and metabolic abnormalities during proinflammatory processes involving several cytokines and chemokines in diabetes. Several studies have indicated that PAI-1 plays crucial roles in insulin actions on liver, muscle, and fat. Accumulated fat and enhanced adipose tissue-derived PAI-1 influence metabolism and vessels in relation to macrophage infiltration, chronic inflammation, and free fatty acid release in obese states. PAI-1-induced fibrinolysis abnormalities are associated with metabolic syndrome, leading to cardiovascular disease through dysregulated vascular coagulation, endothelial dysfunction, and metabolic abnormalities. Adipose tissue-derived PAI-1 is involved in insulin resistance, osteoporosis, and sarcopenia induced by glucocorticoid excess in mice. Moreover, PAI-1 is involved in the other pathological states, such as nonalcoholic fatty liver disease, and cancer. As such, PAI-1 may be exploited as a marker of disease activity as well being a target for clinical drug development. © 2016 American Physiological Society. Compr Physiol 6:1873-1896, 2016.

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Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy

Cited by 141 publications

References 51 publications

Amelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin

Amelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin

Advanced glycation end products regulate extracellular matrix protein and protease expression by human glomerular mesangial cells

Adipose Tissue‐Derived Plasminogen Activator Inhibitor‐1 Function and Regulation

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