scholarly journals Mechanisms Mediating the Renal Profibrotic Actions of Vasoactive Peptides in Transgenic Mice

2000 ◽  
Vol 11 (suppl 2) ◽  
pp. S124-S128
Author(s):  
JEAN-CLAUDE DUSSAULE ◽  
PIERRE-LOUIS THARAUX ◽  
JEAN-JACQUES BOFFA ◽  
FADI FAKHOURI ◽  
RAYMOND ARDAILLOU ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Transgenic Mice ◽  
Receptor Antagonist ◽  
Luciferase Activity ◽  
Collagen I ◽  
Systemic Hemodynamics ◽  
Short Term ◽  
Endothelin 1 ◽  
Vasoactive Peptides ◽  
Preglomerular Arterioles

Abstract. Transgenic mice are useful tools to investigate the mechanisms of the renal profibrotic actions of endothelin and angiotensin II. The overexpression of angiotensinogen and renin genes induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed. Transgenic mice harboring the luciferase gene, under the control of the collagen I α2 chain promoter, and made hypertensive by induction of a nitric oxide (NO) deficiency have been studied. In this strain of mice, luciferase activity is an early index of renal and vascular fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were treated with Nω-nitro-L-arginine methyl ester, an inhibitor of NO synthases. Bosentan (an endothelin receptor antagonist) was as efficient as losartan (an AT1 receptor antagonist) in preventing renal fibrosis, although it did not decrease BP. In short-term experiments, angiotensin II produced an increase in luciferase activity that was entirely prevented by losartan but also by bosentan. It can be concluded that, during chronic inhibition of NO, the collagen I gene is activated, which contributes to the development of nephroangiosclerosis and glomerulosclerosis. Angiotensin II plays a major role in this fibrogenic process, and its effect is at least partly independent of systemic hemodynamics and mediated by the profibrotic action of endothelin-1.

Enalapril attenuates endothelin-1-induced hypertension via increased kinin survival

2003 ◽  
Vol 284 (6) ◽  
pp. H1899-H1903 ◽  
Author(s):  
Ahmed A. Elmarakby ◽  
Peter Morsing ◽  
David M. Pollock
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Neutral Endopeptidase ◽  
Sprague Dawley ◽  
Angiotensin Ii Receptor ◽  
Angiotensin Ii Receptor Antagonist ◽  
Endothelin 1 ◽  
Sprague Dawley Rats ◽  
Vasodilator Activity ◽  
Induced Hypertension

Recent studies have shown that angiotensin-converting enzyme (ACE) inhibitors attenuate endothelin-1 (ET-1)-induced hypertension, but the mechanisms for this effect have not been clarified. Initial experiments were conducted to contrast the effect of the ACE inhibitor enalapril, the combined ACE-neutral endopeptidase inhibitor omapatrilat, and the angiotensin II receptor antagonist candesartan on the hypertensive and renal response to ET-1 in anesthetized Sprague-Dawley rats. Acute intravenous infusion of ET-1 (10 pmol · kg−1 · min−1) for 60 min significantly increased mean arterial pressure (MAP) from 125 ± 8 to 145 ± 8 mmHg ( P < 0.05) and significantly decreased glomerular filtration rate (GFR) from 0.31 ± 0.09 to 0.13 ± 0.05 ml · min−1 · 100 g kidney wt−1. Pretreatment with enalapril (10 mg/kg iv) before ET-1 infusion inhibited the increase in MAP (121 ± 4 vs. 126 ± 4 mmHg) before and during ET-1 infusion, respectively ( P < 0.05) without blocking the effect of ET-1 on GFR. In contrast, neither omapatrilat (30 mg/kg) nor candesartan (10 mg/kg) had any effect on ET-1-induced increases in MAP or decreases in GFR. To determine whether the effect of enalapril was due to the decrease in angiotensin II or increase in kinin formation, rats were given REF-000359 (1 mg/kg iv), a selective B2 receptor antagonist, with or without enalapril before ET-1 infusion. REF-000359 completely blocked the effect of enalapril on ET-1 infusion (MAP was 117 ± 5 vs. 135 ± 5 mmHg before and during ET-1 infusion, respectively, P < 0.05). REF-000359 alone had no effect on the response to ET-1 infusion (MAP was 117 ± 4 vs. 144 ± 4 mmHg before and during ET-1 infusion, respectively, P < 0.05). REF-000359 with or without enalapril had no significant effect on the ability of ET-1 infusion to decrease GFR. These findings support the hypothesis that decreased catabolism of bradykinin and its subsequent vasodilator activity oppose the actions of ET-1 to increase MAP.

scholarly journals Angiotensin II Activates Collagen Type I Gene in the Renal Cortex and Aorta of Transgenic Mice through Interaction with Endothelin and TGF-β

2001 ◽  
Vol 12 (12) ◽  
pp. 2701-2710
Author(s):  
Fadi Fakhouri ◽  
Sandrine Placier ◽  
Raymond Ardaillou ◽  
Jean-Claude Dussaule ◽  
Christos Chatziantoniou
Keyword(s):  
Angiotensin Ii ◽  
Transgenic Mice ◽  
Collagen Type ◽  
Renal Cortex ◽  
Collagen Type I ◽  
Collagen I ◽  
Type I ◽  
Cortical Slices ◽  
I Gene

ABSTRACT. Hypertension is frequently associated with the development of renal vascular fibrosis. This pathophysiologic process is due to the abnormal formation of extracellular matrix proteins, mainly collagen type I. In previous studies, it has been observed that the pharmacologic blockade of angiotensin II (Ang II) or endothelin (ET) blunted the development of glomerulo- and nephroangiosclerosis in nitric oxide-deficient hypertensive animals by inhibiting collagen I gene activation. The purpose of this study was to investigate whether and how AngII interacts with ET to activate the collagen I gene and whether transforming growth factor-β (TGF-β) could be a player in this interaction. Experiments were performedin vivoon transgenic mice harboring the luciferase gene under the control of the collagen I-α2 chain promoter (procolα2[I]). Bolus intravenous administration of AngII or ET produced a rapid, dose-dependent activation of collagen I gene in aorta and renal cortical slices (threefold increase over control at 2 h,P< 0.01). The AngII-induced effect on procolα2(I) was completely inhibited by candesartan (AngII type 1 receptor antagonist) and substantially blunted by bosentan (dual ET receptor antagonist) (P< 0.01), whereas the ET-induced activation of collagen I gene was blocked only by bosentan. In subsequent experiments, TGF-β (also administered intravenously) produced a rapid increase of procolα2(I) in aorta and renal cortical slices (twofold increase over control at 1 h,P< 0.01) that was completely blocked by decorin (scavenger of the active form of TGF-β). In addition, decorin attenuated the activation of collagen I gene produced by AngII (P< 0.01). These data indicate that AngII can activate collagen I gene in aorta and renal cortexin vivoby a mechanism(s) requiring participation and/or cooperation of ET and TGF-β.

Analysis of effects of bosentan (Ro 47-0203), a nonpeptide endothelin ETA/ETB receptor antagonist, in the hind-limb vascular bed of the cat

1998 ◽  
Vol 76 (2) ◽  
pp. 141-147 ◽  
Author(s):  
Hunter C Champion ◽  
Lance S Estrada ◽  
Leslie N Estrada ◽  
Janos G Filep ◽  
Philip J Kadowitz
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Hind Limb ◽  
Perfusion Pressure ◽  
Endothelin 1 ◽  
Vascular Bed ◽  
Limb Perfusion ◽  
Calcitonin Gene ◽  
Etb Receptor ◽  
Higher Doses

The effects of bosentan (Ro 47-0203), an endothelin A and B receptor antagonist, on responses to endothelin-1, sarafotoxin 6c, angiotensin II, and arginine vasopressin were investigated in the hind-limb vascular bed of the cat. Under constant-flow conditions, intraarterial injections of endothelin-1 and sarafotoxin 6c induced biphasic changes in hind-limb perfusion pressure characterized by an initial decrease followed by a secondary increase in perfusion pressure. The vasodilator and vasoconstrictor components of the biphasic responses to endothelin-1 and sarafotoxin 6c were reduced by bosentan, and the endothelin receptor antagonist reduced baseline systemic arterial and hind-limb perfusion pressures. Bosentan decreased vasoconstrictor responses to lower doses of angiotensin II, whereas responses to higher doses of angiotensin II and responses to vasopressin, U46619, BAY K8644, norepinephrine, acetylcholine, bradykinin, levcromakalim, PGE1, adrenomedullin, and calcitonin gene-related peptide were not altered. Vasoconstrictor responses to ET-1 were not altered by the angiotensin AT1 receptor antagonist DuP 532 or the AT2 receptor antagonist PD123,319. The results of the present study show that bosentan attenuates vasodilator and vasoconstrictor responses to endothelin-1 and sarafotoxin 6c and vasoconstrictor responses to lower doses of angiotensin II in the hind-limb vascular bed of the cat. These results suggest that endothelin may be involved in mediating responses to lower doses of angiotensin II and in the maintenance of baseline tone in the systemic vascular bed of the cat.Key words: angiotensin II, bosentan (Ro 47-0203), endothelin, regional vascular bed, endothelial-derived peptide.

scholarly journals Angiotensin II sensitivity of afferent glomerular arterioles in endothelin-1 transgenic mice

2005 ◽  
Vol 20 (12) ◽  
pp. 2681-2689 ◽  
Author(s):  
Andreas Patzak ◽  
Julia Bontscho ◽  
EnYin Lai ◽  
Eckehardt Kupsch ◽  
Angela Skalweit ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Transgenic Mice ◽  
Endothelin 1 ◽  
Glomerular Arterioles

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

2007 ◽  
Vol 293 (2) ◽  
pp. H1291-H1299 ◽  
Author(s):  
Amy K. L. Banes-Berceli ◽  
Pimonrat Ketsawatsomkron ◽  
Safia Ogbi ◽  
Bela Patel ◽  
David M. Pollock ◽  
...  
Keyword(s):  
Drinking Water ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Vascular Complications ◽  
Diabetic Rats ◽  
Ang Ii ◽  
Endothelin 1 ◽  
Endothelium Dependent Relaxation ◽  
Stat Pathway

The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [ days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT1 receptor antagonist, 10 mg·kg−1·day−1 orally in drinking water), atrasentan (ETA receptor antagonist, 10 mg·kg−1·day−1 orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg·kg−1·day−1 intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 ± 9.0, 130 ± 3.3, 128 ± 6.8, and 131 ± 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 ± 3.0, 92.6 ± 7.4, 76.9 ± 12.1, and 38.3 ± 13.1% in sham, sham + AG-490, STZ + AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.

Aldosterone induces interleukin-18 through endothelin-1, angiotensin II, Rho/Rho-kinase, and PPARs in cardiomyocytes

2008 ◽  
Vol 295 (3) ◽  
pp. H1279-H1287 ◽  
Author(s):  
Takashi Doi ◽  
Tsuyoshi Sakoda ◽  
Takafumi Akagami ◽  
Toshio Naka ◽  
Yoshitomo Mori ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Receptor Antagonist ◽  
Myocardial Dysfunction ◽  
Rho Kinase ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Endothelin 1 ◽  
Ppar Agonists ◽  
Mrna And Protein Expression

Aldosterone (Aldo) is recognized as an important risk factor for cardiovascular diseases. IL-18 induces myocardial hypertrophy, loss of contractility of cardiomyocytes, and apoptosis leading myocardial dysfunction. However, so far, there have been few reports concerning the interaction between Aldo and IL-18. The present study examined the effects and mechanisms of Aldo on IL-18 expression and the roles of peroxisome proliferator-activated receptor (PPAR) agonists in rat cardiomyocytes. We used cultured rat neonatal cardiomyocytes stimulated with Aldo to measure IL-18 mRNA and protein expression, Rho-kinase, and NF-κB activity. We also investigated the effects of PPAR agonists on these actions. Aldo, endothelin-1 (ET-1), and angiotensin II (ANG II) increased IL-18 mRNA and protein expression. Mineralocorticoid receptor antagonists, endothelin A receptor antagonist, and ANG II receptor antagonist inhibited Aldo-induced IL-18 expression. Aldo induced ET-1 and ANG II production in cultured media. Moreover, Rho/Rho-kinase inhibitor and statin inhibited Aldo-induced IL-18 expression. On the other hand, Aldo upregulated the activities of Rho-kinase and NF-κB. PPAR agonists attenuated the Aldo-induced IL-18 expression and NF-κB activity but not the Rho-kinase activity. Our findings indicate that Aldo induces IL-18 expression through a mechanism that involves, at a minimum, ET-1 and ANG II acting via the Rho/Rho-kinase and PPAR/NF-κB pathway. The induction of IL-18 in cardiomyocytes by Aldo, ET-1, and ANG II might, therefore, cause a deterioration of the cardiac function in an autocrine and paracrine fashion. The inhibition of the IL-18 expression by PPAR agonists might be one of the mechanisms whereby the beneficial cardiovascular effects are exerted.

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