Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The increased growth potential of vascular smooth muscle cells (VSMCs) represents one of the crucial anomalies responsible for the development of essential hypertension, diabetic macroangiopathy, and atherosclerosis. The exaggerated response to growth factors of VSMC from spontaneously hypertensive rats (SHRs) persists in culture when compared with normotensive Wistar-Kyoto control rats, indicating an intrinsic defect in the hypertension-producing mechanism. This greater proliferation is characterized by two intermediate phenotypes: (1) accelerated entry into the S phase of the cell cycle, which results from hyperresponsiveness to epidermal growth factor and platelet-derived growth factor, and (2) abnormal contact inhibition. The enhanced expression of transforming growth factor beta 1 (TGF-beta 1) messenger ribonucleic acid in SHRs precedes this altered contact inhibition, and only VSMCs from SHRs respond to exogenously added TGF-beta 1 at a high cell density, which suggests that abnormal TGF-beta 1 autoregulation may be implicated in the second phenotype. Platelets contain major growth factors for VSMC. Platelet extracts from hypertensive and diabetic patients present augmented growth-promoting activity on VSMCs, which is most evident when both diseases occur simultaneously. Growth-promoting activity may be further influenced by antihypertensive therapy. This growth-promoting activity is increased by hydrochlorothiazide but not by indapamide, atenolol, or captopril in diabetic hypertensive and nondiabetic hypertensive patients. In conclusion, VSMCs in hypertension manifest an intrinsic growth defect that is modulated by extrinsic platelet growth factors and antihypertensive drugs.
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PMID:Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension. 192 87

The spontaneously hypertensive rat (SHR) was developed as a genetic model of essential hypertension. In vivo and in vitro evidence demonstrates that vascular smooth muscle cells (VSMCs) from the SHR produce more nerve growth factor (NGF) than the normotensive Wistar-Kyoto (WKY) control strain. This increased NGF production is accompanied by excessive innervation of target tissues in the SHR. In the present study, a sensitive, competitive, quantitative, reverse-transcriptase polymerase chain reaction (C Q RT-PCR) assay is characterized and used to analyze levels of NGF mRNA in cultured VSMCs derived from the SHR and WKY strains as well as bladder tissue. Differences in NGF secretion rates between SHR and WKY VSMCs were partially due to an increased stability of NGF mRNA in SHR VSMCs. Following treatment with platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta 1) to elevate NGF production, the half-life of the NGF mRNA was 104.5 +/- 18.0 min in SHR VSMCs, compared to only 36.5 +/- 11.6 min in WKY VSMCs. Sequence analysis of the 3' untranslated region (UTR) revealed no strain differences in cis-acting sequences potentially involved in determining mRNA stability. Thus, it seems unlikely to be a 3'UTR mutation that prolongs mRNA lifetime. Rather, differential regulation of an RNA-binding protein may play a role in the abnormal NGF mRNA stability in SHR VSMCs. SHR VSMCs also demonstrate an increased translational efficiency of NGF protein; more NGF protein is synthesized per unit of NGF mRNA. The use of a C Q RT-PCR assay has allowed the determination that abnormal NGF mRNA stabilization as well as altered translational efficiency may contribute to excess NGF synthesis and progressive hypertension in the SHR.
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PMID:Mechanisms of increased NGF production in vascular smooth muscle of the spontaneously hypertensive rat. 963 27

Nephrovasculopathies are an increasing cause of end-stage renal failure. Nephrosclerosis is a common finding in the hypertensive patient. However, genetic factors play a prominent role in its incidence. Nephrosclerosis is a common cause of early renal failure in blacks of African ancestry, as opposed to white Europeans, in whom hypertensive nephrosclerosis rarely and slowly leads to uremia. That primary hypertension is accompanied by arterionephrosclerosis and arteriolonephrosclerosis, by focal and segmental glomerulosclerosis leading to glomerular obsolescence and by interstitial fibrosis has been established for nearly a century. However, renal vascular lesions can be observed in animal models as well as in some humans, especially blacks, in the absence of, or preceding the onset of hypertension. This suggests that nephroangiosclerosis might stem from a genetic defect in the renal vascular bed, a defect closely associated with the hypertensive trait. Atherosclerotic renal artery stenosis is a major, potentially remediable cause of chronic renal failure, especially in whites. Its prevalence in the atherosclerotic population is in the order of 15 percent. This figure has obvious bearing in terms of health cost. Early diagnosis and treatment by angioplasty or surgery can preclude development to end-stage renal disease and maintenance hemodialysis, as renal atrophy due to chronic ischemia resulting from renal artery stenosis can be halted or partially reversed by revascularization before extensive fibrosis sets in. Finally, renal vascular lesions are commonly observed in the course of various nephropathies, even in the absence of hypertension. The relationship between fibrogenesis and these vascular lesions, which develop along with interstitial fibrosis and entail an unfavorable prognosis in various glomerulopathies, remains to be elucidated. This is especially the case for focal-segmental glomerulosclerosis, membranous glomerulopathy and IgA glomerulonephritis. The pathophysiology of renal fibrosis induced by ischemia is centered on increased generation of angiotensin II that is fibrogenic owing to interaction with endothelin 1, PDGF-BB and TGF-beta. These notions open perspectives toward pharmacologic means to retard or even prevent the development of such various ischemic conditions to end-stage renal failure.
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PMID:[Vascular mechanisms of renal fibrosis. Vasculonephropathies and arterial hypertension]. 1037 63

We investigated whether a relationship exists between circulating transforming growth factor beta -1 (TGF-beta(1)), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-beta(1) and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion >30 and <300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index >116 g/m(2) for men and >104 g/m(2) for women) (group B; n=17) and those without microalbuminuria or left ventricular hypertrophy (group A; n=13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-beta(1) was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (P<0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Whereas TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I decreased (P<0.05) in responders, no changes in these parameters were observed in nonresponders. These findings show that an association exists between an excess of TGF-beta(1), stimulation of collagen type I synthesis, inhibition of collagen type I degradation, and cardiorenal damage in a group of patients with essential hypertension. In addition, our results suggest that the ability of losartan to blunt the synthesis of TGF-beta(1) and normalize collagen type I metabolism may contribute to protect the heart and the kidney in a fraction of patients with essential hypertension.
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PMID:Transforming growth factor beta in hypertensives with cardiorenal damage. 1104 Feb 29

Proteinuria is the hallmark of renal disease and proteinuria exceeding 1 gm a day in patients with renal disease augers a poorer prognosis. Proteinuria has been shown to be tubulotoxic and directly contributes to renal deterioration. Patients with non-selective proteinuria are more likely to have progressive renal disease. Diabetic patients with persistent microhaematuria have about 20 times the risk of developing diabetic nephropathy. In essential hypertension, the onset of de novo proteinuria after years of adequate BP control is a marker of subsequent decline in renal function. In glomerulonephritis, more severe proteinuria is associated with faster rate of progression. Even though the initial phase of proteinuria in patients with glomerulonephritis is usually of immunological origin, in the vast majority of patients with established disease, the latter progressive phase of proteinuric glomerulopathy is the result of glomerular hyperfiltration which shifts glomerular non-selective pores to larger dimensions resulting in excessive leakage of protein in the urine. Endothelial injury resulting from glomerular hyperfiltration causes increase in local generation of Angiotensin II in the kidney as part of the hemodynamic response. ACE inhibitors and angiotensin II receptor antagonists (ATRA) can improve glomerular pore-selectivity by remodelling the glomerular basement membrane. In addition, these agents also have beneficial effects by decreasing TGF-beta production therapy decreasing mesangial cell proliferation, hence ameliorating disease progression in patients with diabetic nephropathy and IgA nephropathy. A number of recent clinical trials have shown that ACEI and ATRA therapy can retard the progression of renal deterioration in patients with NIDDM and those with IgA nephropathy and even restore normal renal function in those with mild renal impairment. Treatment and control of proteinuria in patients with renal disease should be regarded as important as treatment of hypertension as it can prevent renal failure.
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PMID:Proteinuria: clinical signficance and basis for therapy. 1176 58

Hypertension that results in left ventricular (LV) hypertrophy and/or fibrosis can lead to cardiac dysfunction. Spontaneously hypertensive rats (SHR) develop high blood pressure and LV hypertrophy at an early age and are a popular model of human essential hypertension. To investigate the role of the tissue kallikrein-kinin system in cardiac remodeling, an adenovirus containing the human tissue kallikrein gene was injected intravenously into adult SHR and normotensive Wistar-Kyoto (WKY) rats. The blood pressure of WKY rats remained unchanged throughout the experiment. Alternatively, kallikrein gene transfer reduced blood pressure in SHR for the first 2 wk, but had no effect from 3 to 5 wk. Five weeks after kallikrein gene delivery, SHR showed significant reductions in LV-to-heart weight ratio, LV long axis, and cardiomyocyte size; however, these parameters were unaffected in WKY rats. Interestingly, cardiac collagen density was decreased in both SHR and WKY rats receiving the kallikrein gene. Kallikrein gene transfer also increased cardiac capillary density in SHR, but not in WKY rats. The morphological changes after kallikrein gene transfer were associated with decreases in JNK activation as well as transforming growth factor (TGF)-beta 1 and plasminogen activator inhibitor-1 levels in the heart. In addition, kallikrein gene delivery elevated LV nitric oxide and cGMP levels in both rat strains. These results indicate that kallikrein-kinin attenuates cardiac hypertrophy and fibrosis and enhances capillary growth in SHR through the suppression of JNK, TGF-beta 1, and plasminogen activator inhibitor-1 via the nitric oxide-cGMP pathway.
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PMID:Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats. 1281 55