Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-beta and deposition of extracellular matrix proteins follows, which is accompanied by fibrinoid vasculitis in small vessels of the heart and kidneys. Angiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowered blood pressure and shifted pressure natriuresis partially leftward by different mechanisms. When combined, they normalized blood pressure, pressure natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy completely. Endothelin receptor blockade had no influence on blood pressure but protected from vasculopathy and improved survival. We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFkappaB is upregulated in this model. We speculate that the transcription factors NFkappaB and AP-1 are involved with initiating chemokine and cytokine expression, leading to the above cascade. The unique model and our pharmacological probes will enable us to test these hypotheses.
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PMID:Hypertension-induced end-organ damage : A new transgenic approach to an old problem. 993 Nov 7

The antiproteinuric effect of angiotensin-converting enzyme inhibitors underscores the importance of a hemodynamic injury and the renin-angiotensin system in the proteinuria of various glomerular diseases. Vascular endothelial growth factor (VEGF), a potent promoter of vascular permeability, is induced in mesangial cells by both mechanical stretch and TGF-beta1. This study investigates the effect of TGF-beta blockade, angiotensin II (AngII), and the interaction between AngII and stretch on human mesangial cell VEGF production. Exposure to AngII (1 microM) induced a significant increase in VEGF mRNA and protein levels (1.5+/-0.1 and 1.7+/-0.3, respectively, fold increase over control, P<0.05). The AngII receptor (AT1) antagonist Losartan (10 microM) prevented AngII-induced, but not stretch-induced, VEGF protein secretion (AngII 1.7+/-0.3, AngII + Losartan 1.0+/-0.1, P<0.05; stretch 2.4+/-0.4, stretch + Losartan 2.6+/-0.5). Stretch-induced VEGF production was also unaffected by the addition of an anti-TGF-beta neutralizing antibody (stretch 2.85+/-0.82 versus stretch + anti-TGF-beta 2.84+/-0.01, fold increase over control). Simultaneous exposure to both AngII and stretch for 12 h had an additive effect on VEGF production (AngII 1.6+/-0.1, stretch 2.6+/-0.27, AngII + stretch 3.1+/-0.35). Conversely, preexposure to stretch magnified AngII-induced VEGF protein secretion (unstretched + AngII 1.3+/-0.0, stretched + AngII 1.9+/-0.1, P<0.01) with a parallel 1.5-fold increase in AT1 receptor levels. AngII and stretch can both independently induce VEGF production; in addition, mechanical stretch upregulates the AT1 receptor, enhancing the cellular response to AngII.
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PMID:Interaction of angiotensin II and mechanical stretch on vascular endothelial growth factor production by human mesangial cells. 1020 56

This study aimed to identify the intracellular signaling pathway in angiotensin II (Ang II)-induced upregulation of plasminogen activator inhibitor type 1 (PAI-1) mRNA expression in cultured rat glomerular mesangial cells, and to examine the interaction between Ang II and TGF-beta signaling. Ang II-induced upregulation of PAI-1 mRNA expression was prevented by a protein kinase C (PKC) inhibitor, bisindorylmaleimide I. While phorbol 12-myristate 13-acetate (PMA) upregulated the PAI-1 mRNA expression, a calcium ionophore, ionomycin, had little effect. Mesangial cells pretreated with PMA for 24 h to downregulate PKC demonstrated attenuated response to Ang II. A protein tyrosine kinase inhibitor, genistein, completely blocked both Ang II- and PMA-induced PAI-1 mRNA expression. Transforming growth factor-beta1 (TGF-beta1) alone induced the expression, and in the presence of Ang II, TGF-beta1 superinduced PAI-1 mRNA expression to a higher extent. Both bisindorylmaleimide I and genistein suppressed the Ang II plus TGF-beta1-induced PAI-1 mRNA upregulation to the basal level, while downregulation of PKC attenuated the synergistic upregulation of PAI-1 mRNA expression to the level comparable to TGF-beta1 alone. These data suggest that, in rat mesangial cells, (1) PKC and protein tyrosine kinase(s) are involved in the Ang II signaling cascade, (2) protein tyrosine kinase(s) works downstream from PKC in the cascade, and (3) there is an interaction between the Ang II and TGF-beta signal pathways downstream from PKC. In in vivo settings, local activation of renin-angiotensin and TGF-beta systems in the glomeruli may synergistically augment PAI-1 expression, promote mesangial matrix accumulation and progression of glomerular injury.
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PMID:Association of TGF-beta signaling in angiotensin II-induced PAI-1 mRNA upregulation in mesangial cells: role of PKC. 1020 1

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular growth in rats. In this review, the role of RAS in myocyte protein synthesis (myocyte hypertrophy) and in induction of gene expression will be discussed in rat cardiomyocytes in culture. Traditional RAS can be considered as a system in which circulating Ang II is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of Ang II can be mediated. These actions of Ang II are primarily mediated through Ang II receptors subtype I (AT1-R). When evaluating the effects of Ang II in situ, both changes in circulating levels and local production have to be taken into account. Contrasting results have been found concerning the in vitro effect of Ang II on the protein synthesis in cardiac myocytes and can be at least partly be attributed to methodological problems such as assay of de novo protein synthesis and isolation and separation procedure of cardiac myocytes. The Ang II-induced hypertrophic effect also depends on the existence of nonmyocytes in a cardiocyte culture. In rat cardiocytes, AngII also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide expression) and growth factors (TGF-beta 1 gene expression). In vivo AngII via AT1-R, causes not only ventricular hypertrophy but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and AngII receptor antagonists of the subtype I not only induce the regression but also prevent the development of cardiac hypertrophy in experimental rat models.
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PMID:Antagonism of the renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. 1042 Mar 93

Tubulointerstitial fibrosis is a common end-point of many chronic renal diseases and contributes to the permanent loss of renal function. There is increasing evidence that the profibrogenic cytokine transforming growth factor TGF-beta plays an essential role in this process by inducing the production of extracellular matrix proteins by tubular cells through an autocrine mechanism. We have previously demonstrated that the vasopeptide angiotensin (ANG) II induces TGF-beta transcription and synthesis in cultured murine proximal tubular cells (MCT cell line). Since the overall effects of TGF-beta on a distinct target cell may also depend on the expression of specific cell surface receptors, the present study was undertaken to test the hypothesis that ANG II modulates expression of TGF-beta receptors in MCT cells. ANG II stimulated protein expression of TGF-beta receptor type II, but not that of type I, in MCT cells as detected by immunofluorescence and western blotting of cell lysates. This stimulated receptor expression was also reflected in an overall increase in specific binding of 125I-labeled TGF-beta1 to intact MCT cells. Coincubation with ANG II and an AT1 receptor antagonist abolished this increase in 125I-labeled TGF-beta1 binding. Furthermore, ANG II also increased steady-state mRNA expression for TGF-beta receptor type II. This stimulation was transduced through AT1 receptors and was independent of TGF-beta released into the culture medium. Transient transfection studies using various length enhancer/promoter elements of the human TGF-beta receptor type II linked to the CAT gene revealed that AP1 sites are a necessary prerequisite for ANG II induced transcriptional activity. ANG II had no effect on TGF-beta receptor types I or II protein or on mRNA expression in syngeneic mesangial cells. Our results provide for the first time convincing evidence that ANG II upregulates TGF-beta receptor type II expression on proximal tubular cells. Since this subtype of receptor is primarily engaged in the initial binding of TGF-beta, an increased receptor expression may result in amplification of the TGF-beta effects on tubular cells. Interference with an activated renin-angiotensin system could therefore counteract the profibrogenic effects of TGF-beta by abolishing ANG II induced expression of TGF-beta receptor type II.
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PMID:Angiotensin II stimulates expression of transforming growth factor beta receptor type II in cultured mouse proximal tubular cells. 1049 1

We have noted that n-3 fatty acid-rich oils, such as fish oil, perilla oil and flaxseed oil as well as ethyl docosahexaenoate (DHA) prolonged the survival time of stroke-prone spontaneously hypertensive rats (SHRSP) rats by approximately 10% as compared with linoleate (n-6)-rich safflower oil. Rapeseed oil with a relatively low n-6/n-3 ratio unusually shortened the survival time by approximately 40%, suggesting the presence of minor components unfavorable to SHRSP rats. This study examined the effects of dietary oils and DHA on renal injury and gene expression related to renal injury in SHRSP rats. Rats fed rapeseed oil- and safflower oil-supplemented diets developed more severe proteinuria than those fed soybean oil-supplemented diet used as a control, but there were no significant differences in blood pressure. In contrast, the DHA-supplemented diet inhibited the development of proteinuria and suppressed hypertension. The mRNA levels for renal TGF-beta, fibronectin and renin were higher in the rapeseed oil and safflower oil groups after 9 weeks of feeding of the experimental diet than in the soybean oil and DHA groups. The fatty acid composition of kidney phospholipids was markedly affected by these diets. These results indicate that the renal injury observed in the groups fed safflower oil with a high n-6/n-3 ratio and rapeseed oil with presumed minor components is accompanied by increased expression of the TGF-beta, renin and fibronectin genes, and that dietary DHA suppresses renal injury and gene expression as compared with soybean oil.
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PMID:Dietary docosahexaenoic acid ameliorates, but rapeseed oil and safflower oil accelerate renal injury in stroke-prone spontaneously hypertensive rats as compared with soybean oil, which is associated with expression for renal transforming growth factor-beta, fibronectin and renin. 1060 99

Hypertension, a remediable risk factor for stroke, cardiovascular disease, and renal failure, affects 50 million individuals in the United States alone. African Americans (blacks) have a higher incidence and prevalence of hypertension and hypertension-associated target organ damage compared with Caucasian Americans (whites). Herein, we explored the hypotheses that transforming growth factor-beta(1) (TGF-beta(1)) is hyperexpressed in hypertensives compared with normotensives and that TGF-beta(1) overexpression is more frequent in blacks compared with whites. These hypotheses were stimulated by our recent demonstration that TGF-beta(1) is hyperexpressed in blacks with end-stage renal disease compared with white end-stage renal disease patients and by the biological attributes of TGF-beta(1), which include induction of endothelin-1 expression, stimulation of renin release, and promotion of vascular and renal disease when TGF-beta(1) is produced in excess. TGF-beta(1) profiles were determined in black and white hypertensive subjects and normotensive controls and included circulating protein concentrations, mRNA steady-state levels, and codon 10 genotype. Our investigation demonstrated that TGF-beta(1) protein levels are highest in black hypertensives, and TGF-beta(1) protein as well as TGF-beta(1) mRNA levels are higher in hypertensives compared with normotensives. The proline allele at codon 10 (Pro(10)) was more frequent in blacks compared with whites, and its presence was associated with higher levels of TGF-beta(1) mRNA and protein. Our findings support the idea that TGF-beta(1) hyperexpression is a risk factor for hypertension and hypertensive complications and provides a mechanism for the excess burden of hypertension in blacks.
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PMID:Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage. 1072 60

Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system. These include remodeling of the left ventricle, alterations in the morphology and mechanical properties of the vasculature, and the development of endothelial dysfunction. Recent studies have shown that angiotensin II is capable of mediating these changes via its interaction with the angiotensin II type 1 receptor. These nonhemodynamic effects of angiotensin II are independent of its effect on blood pressure. Thus, elevated levels of angiotensin II may lead directly to many hypertension-associated pathologies. Recent evidence that mechanical strain, oxidized low-density lipoprotein cholesterol, and aldosterone can cause upregulation of angiotensin II type 1 receptors indicates that activation of the renin-angiotensin system is not necessary for the actions of angiotensin II to be amplified. Because the strain on the vessel wall may be increased under conditions of hypertension, increased arterial pressure may amplify the actions of angiotensin II without a discernible increase in plasma angiotensin II levels. In both the myocardium and the peripheral vasculature, fibrosis is a major component of the remodeling that occurs in hypertension. There is substantial evidence that transforming growth factor beta-1 (TGF-beta(1)) mediates angiotensin-II-induced fibrosis in patients with hypertension and in those with a variety of nephropathies. Mechanical strain also induces fibrosis in a mechanism mediated by TGF-beta(1). This cytokine thus represents a common pathway by which angiotensin II and increased arterial pressure may induce cardiovascular fibrosis.
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PMID:Angiotensin II and the pathophysiology of cardiovascular remodeling. 1133 63

The possible contributions of the angiotensin receptor subtypes 1 (AT1) and 2 (AT2) to angiotensin II-induced changes in collagen secretion and production were studied using the specific angiotensin receptor AT1 and AT2 antagonists telmisartan and P-186. The role of the renin-angiotensin system and its interaction with transforming growth factor-beta 1 (TGF-beta 1) in collagen deposition in cardiac fibroblasts in relation to the development of myocardial fibrosis is also discussed. Cardiac fibroblasts (from normal male adult rats) from passage 2 were cultured to confluency and incubated in the presence of angiotensin II (ANG II) in a concentration range of 10(-10)-10(-6) M in serum-free Dulbecco's MEM medium for 24 h. Collagen production and secretion were assayed by [3H]-proline incorporation and noncollagen production and secretion were also analyzed. ANG II dose-dependently increased collagen secretion and production in rat adult cardiac fibroblasts in culture. Noncollagen secretion and production were also concentration-dependently increased by ANG II. Addition of 100 nmol/l ANG II increased (p < 0.01) collagen secretion and production by 75 +/- 6 (SEM) and 113 +/- 23%, respectively, and noncollagen secretion and production by 65 +/- 6 and 57 +/- 16%, respectively. Pretreatment of cardiac fibroblasts with telmisartan completely blocked the ANG II-induced increase in collagen secretion (p < 0.001) and production (p < 0.05) and in noncollagen secretion (p < 0.01) and production (p < 0.01). P-186 had no effect on the ANG II-induced increase in collagen secretion and production. Addition of telmisartan and P-186 did not affect collagen secretion and production in basal cardiac fibroblasts. TGF-beta 1 also concentration- and time-dependently increased the secretion and production of collagen in cardiac fibroblasts. Our data demonstrate that the effects of ANG II on collagen secretion and production in adult rat cardiac fibroblasts in culture are AT1-receptor mediated since they were abolished by the specific AT1-receptor antagonist telmisartan but not by the specific AT2-receptor antagonist P-186. The ability of ANG II to induce collagen synthesis in cardiac fibroblasts may be mediated by increased TGF-beta 1 production.
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PMID:Induction of cardiac fibrosis by angiotensin II. 1134 91

Several recent studies have provided evidence that many of the hemodynamic and mitogenic actions of angiotensin II (Ang II) are mediated by endothelin-1 (ET-1). We hypothesized that Ang II and ET-1 act synergistically to promote a decline in renal function and the development of renal fibrosis in the deoxycorticosterone acetate (DOCA)-salt model of malignant hypertension and renal dysfunction. Experiments were conducted to determine the effects of ET(A) receptor antagonism (A-127722) and AT(1) receptor antagonism (candesartan cilexetil) on the development of renal fibrosis and the decline of renal function. Surgery was conducted on male, Sprague-Dawley rats to remove the right kidney and implant subcutaneously a time-release pellet containing DOCA. DOCA-treated rats were also given 0.9% NaCl to drink. After recovery from surgery, rats received one of four treatments via the drinking solution: (1) candesartan cilexetil (10 mg/kg/day), (2) A-127722 (10 mg/kg/day), (3) candesartan cilexetil plus A-127722, or (4) untreated controls. Over the course of a 3-week treatment period, systolic arterial pressure in all groups were elevated. However, this increase was significantly attenuated in the group given combined A-127722 and candesartan, but not with candesartan alone. Creatinine clearance, used as a measure of GFR, was significantly higher in rats treated with either or both drugs. At the end of the study, renal medullary tissue was harvested for determination of TGF-beta and fibronectin content (ELISA). TGF-beta levels were not reduced by either ET(A), AT(1), or combined ET(A) and AT(1) receptor blockade. Likewise, fibronectin content was similar among groups. These studies indicate that combined ET(A) and AT(1) receptor blockade may produce some improvement on hemodynamics, but have no effect on progression of renal damage in this non-renin-dependent model of hypertension.
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PMID:Combined effects of AT(1) and ET(A) receptor antagonists, candesartan, and A-127722 in DOCA-salt hypertensive rats. 1136 89


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