Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells

Gesualdo, Loreto; Ranieri, Elena; Monno, Raffaella; Rossiello, Maria Rosaria; Colucci, Mario; Semeraro, Nicola; Grandaliano, Giuseppe; Schena, Francesco Paolo; Ursi, Michele; Cerullo, Giuseppina

doi:10.1046/j.1523-1755.1999.00578.x

Cited by 85 publications

(73 citation statements)

References 58 publications

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“…These results are in contrast to those of other studies, which have suggested that the effects of Ang II are mediated by an Ang IV/AT 4 pathway. 24 The complete blockade of Ang II-induced PAI-1 expression by the AT 1 -selective antagonist candesartan may be attributed to its higher ) and/or candesartan (25 g ⅐ kg Ϫ1 ⅐ min…”

Section: Discussionmentioning

confidence: 99%

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Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Chen¹,

Bouchie²,

Perez³

et al. 2000

ATVB

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Abstract-Although the renin-angiotensin system has been implicated in increasing plasminogen activator inhibitor-1 (PAI-1) expression, the role of the angiotensin type 1 (AT 1 ) receptor is controversial. This report examines the effects of angiotensin peptides, angiotensin-converting enzyme inhibition, and AT 1 antagonism on rat aortic and cardiac PAI-1 gene expression. In vitro, angiotensin (Ang) I, Ang II, and angiotensin Arg 2 -Phe 8 (Ang III) were potent agonists of PAI-1 mRNA expression in rat aortic smooth muscle cells (RASMCs), and stimulation of PAI-1 by these peptides was blocked by the AT 1 antagonist candesartan. Angiotensin Val 3 -Phe 8 (Ang IV) and angiotensin Asp 1 -Pro 7 (Ang [1-7]) did not affect PAI-1 expression in RASMCs. In neonatal rat cardiomyocytes, Ang II increased PAI-1 mRNA expression by 4-fold (PϽ0.01), and this response was completely blocked by AT 1 receptor antagonism. Continuous intrajugular infusion of Ang II into Sprague-Dawley rats for 3 hours increased aortic and cardiac PAI-1 mRNA expression by 17-and 9 fold, respectively, and these Ang II responses were completely blocked by coinfusion with candesartan. Aortic and cardiac PAI-1 expressions were compared in spontaneously hypertensive rats and Wistar-Kyoto rats. PAI-1 expression in the aorta and heart from spontaneously hypertensive rats was 5.8-fold and 2-fold higher, respectively, than in control Wistar-Kyoto rats (PϽ0.05). Candesartan treatment for 1 week reduced aortic and cardiac PAI-1 expression in spontaneously hypertensive rats by 94% and 72%, respectively (PϽ0.05), but did not affect vascular PAI-1 levels in Wistar-Kyoto rats. These results demonstrate a role for the AT 1 receptor in mediating the effects of Ang II on aortic and cardiac PAI-1 gene expression. Key Words: angiotensin II Ⅲ plasminogen activator inhibitor Ⅲ hypertension Ⅲ aorta Ⅲ vascular smooth muscle cells P lasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of tissue and urokinase plasminogen activators and thereby reduces the conversion of plasminogen to plasmin, an extracellular protease that mediates fibrinolysis and activates matrix metalloproteinases. 1-3 An elevated level of PAI-1, which occurs in diabetes, insulin resistance, obesity, and hypertension, has been implicated as a contributing risk factor for cardiovascular disease. 4 -7 Recent studies suggest that the renin-angiotensin system (RAS) may exert an important role in the regulation of circulating and vascular PAI-1 expression and may thereby affect the fibrinolytic balance. Reports from our laboratory and others have demonstrated that angiotensin II (Ang II) is a potent stimulator of PAI-1 mRNA and protein expression in both cultured endothelial and vascular smooth muscle cells. 8 -11 The physiological importance of the RAS in modulating PAI-1 levels is supported by in vivo studies, which have demonstrated that treatment of rats with the angiotensin-converting enzyme (ACE) inhibitor captopril suppresses the induction of PAI-1 expression in the aortic neointima induced by b...

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Section: Discussionmentioning

confidence: 99%

“…9 In contrast, other reports have suggested that the AT 1 receptor does not mediate Ang II-stimulated PAI-1 expression. 24,25 Establishing the role of the AT 1 receptor in the regulation of PAI-1 expression may have important clinical significance related to potential differences between ACE inhibitors and AT 1 antagonists on the fibrinolytic system.…”

mentioning

confidence: 99%

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Chen¹,

Bouchie²,

Perez³

et al. 2000

ATVB

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“…PAI-1, u-PA, and TGF-␤ mRNA levels were studied by Northern blotting as described previously (40). Briefly, electrophoresis of 20 g of total RNA from each experimental condition was carried out in 1% agarose gel with 2.2 M formaldehyde.…”

Section: Northern Blottingmentioning

confidence: 99%

“…The membrane was stained with ethidium bromide to evaluate the 28S and 18S ribosomal bands and prehybridized at 42°C for 2 h in 50% Formamide, 0.5% SDS, 5x SSC, and 0.1 mg/ml salmon sperm DNA. Fragments of the human PAI-1, u-PA, t-PA, and TGF-␤ cDNA were used as probes (40). The DNA fragments were labeled by random priming using a commercially available kit (Amersham) and [ 32 P]dCTP (specific activity: 3,000 Ci/mmol).…”

Section: Northern Blottingmentioning

confidence: 99%

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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“…Although mean cortisol concentration was higher during low salt intake than during high salt intake and serum cortisol concentration increased with the number of PAI-1 4G alleles under high-salt conditions, there was no correlation between cortisol and PAI-1 antigen under either low-or high-salt conditions. Both Ang II (or its hexapeptide metabolite, Ang IV) and aldosterone increase PAI-1 expression in a variety of cell types, including astrocytes, 35 endothelial cells, 4 vascular smooth muscle cells, 36 proximal tubular epithelial cells, 37 and mesangial cells. 38 Systemic infusion of Ang II increases vascular, renal, and hepatic PAI-1 expression in rats, 39 whereas treatment of animals with ACE inhibitors, AT 1 receptor antagonists, or aldosterone receptor antagonists decreases tissue PAI-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen

Brown

Murphey²,

Srikuma³

et al. 2001

ATVB

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Abstract-Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased circulating PAI-1 antigen and increased risk of thrombotic cardiovascular events. A 4G/5G polymorphism located 675 bp upstream from the transcription start site of the PAI-1 gene affects PAI-1 antigen concentrations. To test the hypothesis that PAI-1 4G/5G genotype influences the effect of activation of the RAAS on PAI-1 expression, we measured morning PAI-1 antigen concentrations in 76 subjects with essential hypertension during low (10 mmol/d) and high (200 mmol/d) salt intake. Low salt intake was associated with activation of the RAAS as measured by plasma renin activity (2.3Ϯ0.2 versus 0.5Ϯ0.0 ng angiotensin I · mL Ϫ1 · h Ϫ1 , PϽ0.001) and aldosterone (529Ϯ40 versus 145Ϯ12 pmol/L). PAI-1 antigen concentrations were 17.9Ϯ2.7, 19.2Ϯ2.5, and 27.8Ϯ4.0 ng/mL during high salt intake and 19.2Ϯ2.7, 21.6Ϯ2.9, and 38.9Ϯ7.2 ng/mL during low salt intake in the 5G/5G (nϭ14), 4G/5G (nϭ40), and 4G/4G (nϭ22) groups, respectively. There was a significant effect of both salt intake (Fϭ6.0, Pϭ0.017) and PAI-1 4G/5G genotype (Fϭ7.6, Pϭ0.001) on PAI-1 antigen. More importantly, there was a significant interactive effect (Fϭ7.8, Pϭ0.001) of salt intake and PAI-1 4G/5G genotype on PAI-1 antigen. PAI-1 4G/5G genotype influenced the relationship between serum triglycerides and PAI-1 antigen such that the relationship was significant only in 4G homozygotes during either high (R 2 ϭ0.31, Pϭ0.014) or low (R 2 ϭ0.37, Pϭ0.006) salt intake. This study identifies an important gene-by-environment interaction that may influence cardiovascular morbidity and the response to pharmacological therapies that interrupt the RAAS. Key Words: thrombosis Ⅲ genetics Ⅲ fibrinolysis Ⅲ coagulation A ctivation of the renin-angiotensin-aldosterone (RAAS) system has been associated with an increased risk of myocardial infarction (MI) and stroke in patients with essential hypertension. 1,2 Conversely, interruption of the RAAS by ACE inhibition reduces the risk of MI in patients at risk for coronary artery disease. 3 Recent studies suggest that the effects of activation and interruption of the RAAS on cardiovascular morbidity and mortality derive in part from an interaction of the RAAS and fibrinolytic systems. 4,5 Endogenous fibrinolysis plays a critical role in limiting thrombosis and depends on the balance between plasminogen activators (primarily tissue plasminogen activator, tPA) and plasminogen activator inhibitors (PAI, predominantly PAI-1). 6,7 Both of these essential fibrinolytic components are synthesized locally in the vascular wall (in endothelial and smooth muscle cells), have short half-lives, and circulate in trace concentrations in the plasma. Increased PAI-1 expression has been demonstrated in atherosclerotic lesions. 8,9 Elevated PAI-1 concentrations are seen in youthful survivors of acute MI compared with age-matched control subjects, 10 and elevated levels of PAI-1 appear to be a risk factor for recurrent MI. 11 PAI-1 antigen and activity are ...

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Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells

Cited by 85 publications

References 58 publications

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen

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Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells

Cited by 85 publications

References 58 publications

Role of the Angiotensin AT 1 Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Role of the Angiotensin AT 1 Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen

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Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression

Role of the Angiotensin AT ₁ Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression