Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sclerosis and increased matrix expression in diabetes are mediated by glucose-induced transforming growth factor (TGF)-beta1 expression. The intracellular effects of high glucose occur at least in part by way of protein kinase C (PKC). We previously described a role for PKC-alpha in glucose-induced permeability. We now investigated the hypothesis that glucose-induced expression of TGF-beta1 and its receptors (TGF-beta-R1 and -R2) are mediated by activation of this PKC isoform. TGF-beta1 and TGF-beta-R expressions were determined in vascular smooth muscle cells (VSMCs) by immunocytochemistry and Western blotting. PKC isoforms were assessed by confocal microscopy. PKC isoforms were inhibited with antisense oligodeoxynucleotides. PKC-alpha was upregulated by overexpression or microinjection. High glucose (20 mmol/L) increased VSMC TGF-beta1 and TGF-beta-R1 expression but not TGF-beta-R2 expression. PKC inhibitors and specific PKC-alpha downregulation by antisense treatment prevented this effect, whereas antisense treatment against PKC-beta, -epsilon, and -zeta had no influence. PKC-alpha overexpression increased TGF-beta1 and TGF-beta-R1 expression but not TGF-beta-R2 expression. PKC-alpha microinjection into individual VSMCs also increased TGF-beta1 and TGF-beta-R immunofluorescence. Last, VSMCs from PKC-alpha-deficient mice did not respond to high glucose compared with VSMCs from wild-type mice. We propose that high glucose-induced TGF-beta1 and TGF-beta-R1 expression is mediated by PKC-alpha. Our findings suggest an autocrine feedback mechanism and a possible role for PKC-alpha in diabetic vascular disease.
Hypertension 2003 Sep
PMID:Glucose-induced TGF-beta1 and TGF-beta receptor-1 expression in vascular smooth muscle cells is mediated by protein kinase C-alpha. 1293 31

Angiotensin II (Ang II) is implicated in the proinflammatory process in various disease situations. Thus, we sought to determine the role of Ang II in early inflammation-induced fibrosis of pressure-overloaded (PO) hearts. PO was induced by suprarenal aortic constriction (AC) at day 0 in male Wistar rats, and they were orally administered 0.1 mg/kg per day candesartan every day from day -7. This was the maximum dose of candesartan that did not change arterial pressure in hypertensive rats with AC (AC rats). In AC rats, cardiac angiotensin-converting enzyme (ACE) activity was transiently enhanced after day 1 and peaked at day 3, declining to lower levels by day 14, whereas serum ACE activity was not changed. In AC rats, PO induced early fibroinflammatory changes (monocyte chemoattractant factor [MCP]-1 and transforming growth factor [TGF]-beta expression, perivascular macrophage accumulation, and fibroblast proliferation), and thereafter, left ventricular hypertrophy developed, featuring myocyte hypertrophy, intramyocardial arterial wall thickening, and perivascular and interstitial fibroses. Candesartan suppressed the induction of MCP-1 and TGF-beta and reduced macrophage accumulation and fibroblast proliferation in PO hearts. Candesartan significantly prevented perivascular and interstitial fibrosis. However, candesartan did not affect myocyte hypertrophy and arterial wall thickening. In conclusion, a subdepressor dose of candesartan prevented the MCP-1-mediated inflammatory process and reactive myocardial fibrosis in PO hearts. Ang II might play a key role in reactive fibrosis in hypertensive hearts, independent of arterial pressure changes.
Hypertension 2004 Feb
PMID:Pressure-independent effects of angiotensin II on hypertensive myocardial fibrosis. 1469

Excessive myocardial fibrosis deteriorates diastolic function in hypertensive hearts. Involvement of macrophages is suggested in fibrotic process in various diseased situations. We sought to examine the role of macrophages in myocardial remodeling and cardiac dysfunction in pressure-overloaded hearts. In Wistar rats with suprarenal aortic constriction, pressure overload induced perivascular macrophage accumulation and fibroblast proliferation with a peak at day 3, decreasing to lower levels by day 28. Myocyte chemoattractant protein (MCP)-1 mRNA was upregulated after day 1, peaking at day 3 and returning to insignificant levels by day 28, whereas transforming growth factor (TGF)-beta induction was observed after day 3, with a peak at day 7, and remained relatively elevated at day 28. After day 7, concentric left ventricular (LV) hypertrophy developed, associated with reactive fibrosis and myocyte hypertrophy. At day 28, echocardiography showed normal LV fractional shortening but decreased ratio of early to late filling wave of transmitral Doppler velocity, and hemodynamic studies revealed elevated LV end-diastolic pressure, suggesting normal systolic but impaired diastolic function. Chronic treatment with an anti-MCP-1 monoclonal neutralizing antibody inhibited not only macrophage accumulation but also fibroblast proliferation and TGF-beta induction. Furthermore, the neutralizing antibody attenuated myocardial fibrosis, but not myocyte hypertrophy, and ameliorated diastolic dysfunction without affecting blood pressure and systolic function. In conclusion, roles of MCP-1-mediated macrophage accumulation are suggested in myocardial fibrosis in pressure-overloaded hearts through TGF-beta-mediated process. Inhibition of inflammation may be a new strategy to prevent myocardial fibrosis and resultant diastolic dysfunction in hypertensive hearts.
Hypertension 2004 Apr
PMID:Hypertensive myocardial fibrosis and diastolic dysfunction: another model of inflammation? 1496 44

Renal perfusion pressure was servo-controlled chronically in rats to quantify the relative contribution of elevated arterial pressure versus angiotensin II (Ang II) on the induction of renal injury in Ang II-induced hypertension. Sprague-Dawley rats fed a 4% salt diet were administered Ang II for 14 days (25 ng/kg per minute IV; saline only for sham rats), and the renal perfusion pressure to the left kidney was continuously servo-controlled to maintain a normal pressure in that kidney throughout the period of hypertension. An aortic occluder was implanted around the aorta between the two renal arteries and carotid and femoral arterial pressure were measured continuously throughout the experiment to determine uncontrolled and controlled renal perfusion pressure, respectively. Renal perfusion pressure of uncontrolled, controlled, and sham kidneys over the period of Ang II or saline infusion averaged 152.6+/-7.0, 117.4+/-3.5, and 110.7+/-2.2 mm Hg, respectively. The high-pressure uncontrolled kidneys exhibited tubular necrosis and interstitial fibrosis, especially prominent in the outer medullary region. Regional glomerular sclerosis and interlobular artery injury were also pronounced. Controlled kidneys were significantly protected from interlobular artery injury, juxtamedullary glomeruli injury, tubular necrosis, and interstitial fibrosis as determined by comparing the level of injury. Glomerular injury was not prevented in the outer cortex. Transforming growth factor (TGF)-beta and active NF-kappaB proteins determined by immunohistochemistry were colocalized in the uncontrolled kidney in regions of interstitial fibrosis. We conclude that the preferential juxtamedullary injury found in Ang II hypertension is largely induced by pressure and is probably mediated through the TGF-beta and NF-kappaB pathway.
Hypertension 2004 Apr
PMID:Role of pressure in angiotensin II-induced renal injury: chronic servo-control of renal perfusion pressure in rats. 1496 28

Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary haemorrhagic telangiectasia related to a mutation within the endoglin gene is described. This report highlights the critical role of the TGF-beta signalling pathway in this condition.
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PMID:Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. 1511 79

The renin-angiotensin system (RAS) is compartmented between circulating blood and tissue pericellular space. Whereas renin and its substrate diffuse easily from one compartment to another, the angiotensin peptides act in the compartment where there are generated: blood or pericellular space. Renin is trapped in tissues by low and high affinity receptors. In the target cells, angiotensin II/AT1 receptor interaction generates different signals including an immediate functional calcium-dependent response, secondary hypertrophy and a late proinflammatory and procoagulant response. These late pathological effects are mediated by NADPH oxydase-generated free oxygen radicals and NFkappaB activation. In vivo, the tissue binding of renin and the induction of converting enzyme are the main determinants of the involvement of the RAS in vascular remodeling. The target cells of interstitial angiotensin II are mainly the vascular smooth muscle cells and fibroblasts, whereas the endothelial cells and circulating leukocytes are the main targets of circulating angiotensin II. In vivo, angiotensin II participates in the vascular wall hypertrophy associated with hypertension. In diabetes, as in other localized fibrotic cardiovascular diseases, the tissue effects of angiotensin II are mainly dependent on its ability to induce TGF-beta expression. In experimental atherosclerosis, angiotensin II infusion induces aneurysm formation mediated by activation of circulating leucocytes. In these models, the administration of angiotensin II antagonists has beneficial effects on pathological remodeling. Such beneficial effects of angiotensin II antagonists in localized pathological remodeling have not yet been demonstrated in humans.
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PMID:[Renin-angiotensin system and vascular remodelling]. 1512 12

In the present study, we investigated, using custom dog cDNA arrays, the time course of transcriptional changes in the left ventricle of dogs fed a normal diet or a high-fat diet (HFD) for 9-24 wk. Array hybridizations were performed with complex probes representing mRNAs expressed in left ventricles from obese hypertensive and lean control dogs. We identified 63 differentially expressed genes, and expression of 17 of 20 randomly chosen genes was confirmed by real-time PCR. Transcripts were categorized into groups involved in metabolism, cell signaling, tissue remodeling, ionic regulation, cell proliferation, and protein synthesis. Hierarchical clustering indicated that the pattern of coregulated genes depends on duration of the HFD, suggesting that HFD-induced obesity hypertension is associated with continuous cardiac transcriptome adaptation despite stability of both body weight and blood pressure. GenMAPP analysis of the data pointed out the crucial importance of the ventricle TGF-beta pathway. Our results suggest that this system may be involved in molecular remodeling during HFD and in changes observed in the transcription profile, reflecting functional and morphological abnormalities that arise during prolonged HFD. These results also suggest some novel regulatory pathways for cardiac adaptation to obesity.
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PMID:Kinetic analysis of cardiac transcriptome regulation during chronic high-fat diet in dogs. 1522 82

Pathologic fibrosis is a key feature of progressive renal disease that correlates closely with kidney dysfunction and in which the prosclerotic growth factor TGF-beta has been consistently implicated. Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid), an antifibrotic agent that is used to treat hypertrophic scars and scleroderma, has also been shown to inhibit TGF-beta-induced extracellular matrix synthesis in a range of cell types, including those of renal origin. Therefore, the effects of tranilast on kidney fibrosis and dysfunction were examined in the subtotal nephrectomy model of progressive renal injury. Subtotal nephrectomy led to proteinuria and renal dysfunction in association with glomerulosclerosis, tubulointerstitial fibrosis, and macrophage accumulation. Despite persistent hypertension, treatment with tranilast led to a reduction in albuminuria (61.7 (x)/(/) 1.2 versus 20.5 (x)/(/) 1.3 mg/d; P < 0.01) and plasma creatinine (0.16 versus 0.08 mmol/L; P < 0.01) in subtotally nephrectomized rats. In addition, features suggestive of TGF-beta activation, including glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy, and macrophage accumulation, all were significantly attenuated by tranilast in association with evidence of reduced TGF-beta signaling in vivo. In the context of a recent pilot study in humans, the findings of the present report suggest that tranilast may provide a novel strategy for the treatment of progressive kidney disease characterized by fibrotic scarring.
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PMID:Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. 1546 66

The renin-angiotensin system (RAS) is compartmented between the circulating blood and pericellular spaces. Whereas renin and its substrate diffuse easily from one compartment to another, angiotensin peptides act in the compartment where there are generated. Renin is trapped in tissues by low- and high-affinity receptors. In target cells, angiotensin II/AT1 receptor interaction generates various signals, including an immediate functional calcium-dependent response, secondary hypertrophy, and a late proinflammatory and procoagulant response. These late pathological effects are mediated by NADPH oxidase-generated oxygen free radicals and NF-k-B activation. In vivo, renin tissue binding and converting-enzyme induction are the main determinants of RAS involvement in vascular remodeling. The main target cells of interstitial angiotensin II are vascular smooth muscle cells and fibroblasts, whereas endothelial cells and circulating leukocytes are the main targets of circulating angiotensin II. In vivo, angiotensin II participates in the vascular wall hypertrophy associated with hypertension. In diabetes, as in other localized fibrotic cardiovascular diseases, the tissular effects of angiotensin II are mainly dependent on its ability to induce TGF-beta expression. In experimental atherosclerosis, angiotensin II infusion induces aneurysm formation mediated by activation of circulating leucocytes. Angiotensin II antagonist therapy has beneficial effects on pathological remodeling in animal models, but it remains to be determined whether this is also the case in humans.
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PMID:[Tissue consequence of renin-angiotensin system activation]. 1558 80

The 31st Annual Meeting of the American Society of Nephrology, held in Philadelphia, Pennsylvania, USA, October 25-28, 1998, presented the newest advances in basic and clinical nephrology science. Several presentations discussed the results of studies with the newer immunosuppressants such as tacrolimus, sirolimus, mycophenolate mofetil and the anti-CD25 monoclonal antibodies, with the conclusion that studies on long-term use of these agents are needed. A number of other issues on immunosuppression protocols in renal transplantation were addressed during the meeting, including the subjects of steroid withdrawal and the role of TGF-beta in the development of chronic allograft nephropathy. The use of NESP in the treatment of renal anemia, the use of sildenafil to treat erectile dysfunction in hemodialysis patients, and the use of ACE inhibitors in nondiabetic renal patients were other important issues discussed at this meeting. Newer approaches to the treatment of hypertension discussed at the meeting highlighted the potential role of angiotensin II receptor antagonists in renal disease patients. Researchers also presented the promising results of a trial of a new, hybrid cell vaccine approach to the treatment of renal cell carcinoma.
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PMID:Recent advances in nephrology. 1561 34


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