Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis

Rérolle, Jean-Philippe; Hertig, Alexandre; Nguyen, Geneviève; Sraër, Jean-Daniel; Rondeau, Éric

doi:10.1111/j.1523-1755.2000.00355.x

Cited by 179 publications

(124 citation statements)

References 65 publications

(1 reference statement)

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“…TGF-β can induce the synthesis of PAI-1, which blocks the conversion of plasminogen into plasmin, thereby creating a block on its own synthesis [51]. The potential of PAI-1 as a therapeutic target in renal fibrogenesis has been extensively reviewed by Rerolle and colleagues [52].…”

Section: Transforming Growth Factor-betamentioning

confidence: 99%

ECM homeostasis in renal diseases: a genomic approach

Eikmans

Baelde

Heer

et al. 2003

The Journal of Pathology

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Chronic renal disease is in general histologically accompanied by a vast amount of scar tissue, ie glomerulosclerosis and interstitial fibrosis. Scarring results from excessive accumulation of extracellular matrix (ECM) components, a process driven by a plethora of cytokines and growth factors. Studies in experimental renal disease which target these regulators using gene therapy limit or prevent the development of scarring. This review focuses specifically on the role of transforming growth factor-beta, platelet-derived growth factor, connective tissue growth factor, hepatocyte growth factor, and epidermal growth factor. The results obtained in animal models hold promise for molecular intervention strategies in human renal disease. Microarray technology allows large-scale gene expression profiling in kidney tissue to identify common molecular pathways in a step towards discovery of new drug targets. Molecular techniques are expected to be used for diagnostic and prognostic purposes in nephrological practice to supplement renal biopsy. Several studies already show that molecular techniques might be of use in routine diagnostic practice. Improvement of diagnosis and prediction of outcome in renal patients might lead to more efficient and earlier therapeutic intervention.

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Section: Transforming Growth Factor-betamentioning

confidence: 99%

ECM homeostasis in renal diseases: a genomic approach

Eikmans

Baelde

Heer

et al. 2003

The Journal of Pathology

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“…In addition, TGF-␤ stimulates an increased PAI-1 gene expression in several cell lines (7). Thus, we investigated whether PAR-2 activation could induce TGF-␤ gene expression and protein release.…”

Section: Par-2 Activation and Tgf-␤ Expressionmentioning

confidence: 99%

“…In the large family of protease inhibitors, plasminogen activator inhibitor-1 (PAI-1) is the most heavily involved in tissue fibrosis (7). PAI-1 gene expression is strikingly induced by TGF-␤ and may play a key role in the powerful profibrotic action of this growth factor (7). Interestingly, an increased expression of this inhibitor of plasminogen activation has been demonstrated in several progressive renal diseases, including IgA nephropathy (IgAN) (8 -10).…”

mentioning

confidence: 99%

“…Thus, an unbalance between these proteases and their specific inhibitors may promote ECM deposition. In the large family of protease inhibitors, plasminogen activator inhibitor-1 (PAI-1) is the most heavily involved in tissue fibrosis (7). PAI-1 gene expression is strikingly induced by TGF-␤ and may play a key role in the powerful profibrotic action of this growth factor (7).…”

mentioning

confidence: 99%

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Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-β, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-β gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-β expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN. E-mail: g.grandaliano@nephro.uniba.it

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“…The proteolytic systems involved in matrix degradation are mainly the matrix metalloproteinase system (MMPs) and the plasminogen activating system (PAs), which are both controlled by potent inhibitors, tissue-inhibitors of metalloproteinases (TIMPs) and plasminogen activator inhibitors (PAIs) (2). TIMPs and PAI-1 have been suggested to play a role in the process of glomerulosclerosis (3).…”

Section: Introductionmentioning

confidence: 99%

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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Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis

Cited by 179 publications

References 65 publications

ECM homeostasis in renal diseases: a genomic approach

ECM homeostasis in renal diseases: a genomic approach

Protease-Activated Receptor-2 Expression in IgA Nephropathy

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

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