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)

During the past two decades epidemiological, clinical and laboratory studies have confirmed the existence of the diabetic heart in some patients with diabetes mellitus. The diagnosis was made in patients in whom other known etiological factors, such as coronary artery disease, alcoholism or hypertensive cardiovascular disease, were ruled out. The newer concept of the diabetic hypertensive heart is clinically based on a higher incidence of congestive heart failure caused by extensive myocardial involvement. In patients with hypertension and hypertension associated with diabetes, the intramyocardial arterioles present medial hypertrophy and a diminished lumen, increased periarteriolar fibrosis, accumulation of fibrillar collagen and patent extramural coronary arteries. Such confirmatory findings have been previously seen in experimental animals and in patients with diabetes and no hypertension. In the genetically diabetic rat, diabetes may be prevented by neonatal thymectomy, suggesting the existence of an autoimmune deficiency syndrome. Furthermore, conversion of Ala 776 into Thr 776 on the polyprotein by a point mutation results in loss of diabetogenicity. Abnormalities in systole and diastole related to lowering of CK-M and CK-B mRNA levels are normalized following insulin therapy. Identification of the genetic factors in the diabetic heart may lead to the identification of its pathogenic mechanisms.
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PMID:Unravelling the conundrums of the diabetic heart diagnosed in 1876: prelude to genetics. 795 32

We have previously reported increased activity of Na+/H+ and Na+/Li+ exchanges in red blood cells (RBC) of patients with hypertension and diabetic nephropathy. The presence in human red blood cells (RBC) of insulin receptors has led us to examine the effects of this hormone on the kinetic parameters of Na+/H+ exchange as a first approach to define its mechanism of action. The antiporter activity was measured as net Na+ influx driven by an outward H+ gradient in acid-loaded, Na-depleted RBCs preincubated with or without (w/wo) insulin (0 to 100 microU/ml) for different time periods. The effects of insulin on the H+ and Na+ activation kinetics of Na+/H+ exchange were examined in RBCs of normal subjects fasted for 12 hours. Insulin (50 microU/ml for 1 hr) increased the Vmax from 28 +/- 6 to 49 +/- 8 mmol/liter cell x hr (N = 10, P < 0.0005) and the Km for Na+ from 72 +/- 10 to 142 +/- 19 mM (N = 4, P < 0.05) but did not change the Km for intracellular H+. Insulin also increased the Vmax of Na+/Li+ exchange at pHi 7.4 (0.34 +/- 0.03 to 0.45 +/- 0.04 mmol/liter cell x hr, N = 9, P < 0.005) as well as the Km for Na+ (31 +/- 3 to 6 +/- 10 mM, P < 0.0003). Therefore, insulin can modulate Na+ sites of Na+/Li+ or Na+/H+ exchanges independent of the occupancy of H+ sites to favor the release of bound Na+ into the cytoplasm. Insulin stimulation of Na+/H+ exchange required endogenous cytosolic Ca2+ levels. The kinetic effects of insulin on Na+/H+ and Na+/Li+ exchanges were imitated by okadaic acid (300 microM), an inhibitor of protein phosphatases which dephosphorylate serine-threonine residues. Okadaic acid increased the Vmax of Na+/H+ and Na+/Li+ exchanges and the Km for Na+ as insulin did. In conclusion, insulin stimulation of the Na+/H+ antiporter occurs by a novel kinetic mechanism leading to a decreased affinity for external Na+ without changes in the affinity for Hi. On the basis that insulin effects were imitated by okadaic acid, we hypothesize that this hormone may increase the phosphorylated state of serine-threonine residues of this antiporter protein.
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PMID:Insulin activation of red blood cell Na+/H+ exchange decreases the affinity of sodium sites. 796 48

Agonist-induced receptor phosphorylation plays a role in transmembrane signal transduction systems. Although the cDNA for the rat vascular type 1 angiotensin II receptor (AT1AR) encodes a G protein-coupled receptor with several potential phosphorylation sites for serine/threonine and tyrosine kinases, little is known about the phosphorylation of this receptor. The aim of this study was to determine the effects of angiotensin II (Ang II) on phosphorylation of the AT1AR in rat aortic vascular smooth muscle cells. Using [32P]orthophosphate-labeled cells, immunoprecipitates with anti-AT1AR antibody revealed a labeled band of molecular weight 52 kD, corresponding to the Ang II receptor. Ang II induced a rapid and significant increase in phosphorylation of the Ang II receptor, with a peak at 20 minutes. Phosphoamino acid analysis showed that the major phosphoamino acid is serine, in both the basal and Ang II-stimulated states. Constitutive and agonist-stimulated tyrosine phosphorylation is also observed to a lesser extent. Immunoblotting of anti-phosphotyrosine immunoprecipitates with anti-AT1AR antibody showed that Ang II caused a delayed tyrosine phosphorylation of the receptor with a peak at 20 minutes in a dose-dependent manner. Forskolin increased total phosphorylation of AT1AR but had no effect on tyrosine phosphorylation. Neither phorbol 12-myristate-13-acetate nor ionomycin altered receptor phosphorylation. These findings suggest that Ang II induces the phosphorylation of its own G protein-coupled receptor through both serine and tyrosine kinases and raise the possibility that phosphorylation of the AT1AR is an important regulator of receptor function.
Hypertension 1994 Oct
PMID:Agonist-induced phosphorylation of the vascular type 1 angiotensin II receptor. 808 22

A recent cross-sectional study of HTs in Salt Lake City and Paris has reported a significant association of a T704-->C (Met235-->Thr) variant in exon 2 of the angiotensinogen gene (AGT) with essential hypertension (HT). The present study used a new, direct PCR technique to detect this variant in 92 Caucasians with severe hypertension (HT) and two HT parents and 94 normotensive (NT) controls. Although frequency of the variant in HTs (0.42) was higher than in NTs (0.39), the difference was not significant (chi 2 = 0.24; P = 0.63). Plasma angiotensinogen showed a weak, nonsignificant relationship with AGT genotype in females and no genotypic relationship was apparent for blood pressure. Thus, if the Met235-->Thr variant of AGT is involved in essential HT, then its contribution may be, at best, much weaker in other HT groups.
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PMID:Cross-sectional analysis of Met235-->Thr variant of angiotensinogen gene in severe, familial hypertension. 826 22

Genetic influences in cerebrovascular disease (CVD) may act either independently or by predisposing to, or modulating, the effect of risk factors such as hypertension. Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction are important in CVD. The angiotensinogen gene has recently been linked with essential hypertension in affected sibships and a particular polymorphism in exon 2 of the angiotensinogen gene, a threonine to methionine substitution at position 235 (M235T), has been associated with pre-eclampsia and hypertension. In this study we examined the relation of M235T polymorphism to cerebrovascular disease and carotid atheroma in 100 consecutive Caucasian patients with internal carotid artery territory ischaemia (TIA or stroke), presenting to a carotid ultrasound service. Forty five age-matched controls (mostly patients' spouses) were also studied. Hypertension was defined as current treatment with anti-hypertensive agents, or SBP > 160 mm Hg or DBP > 95 mm Hg. Twelve of 100 cases (12%) and eight of 45 controls (12%) were homozygous for the T235 allele. T:M allele ratios were 0.34:0.66 in cases and 0.34:0.66 in controls. There was no relation between the polymorphism and either internal carotid stenosis or common carotid artery intima-media thickness. In the cases, mean percentage internal carotid artery stenosis was TT 18.3 (SD 18.7)%, MT 38.0 (27.1)% and MM 36.8 (30.2)%. Mean intima-media thickness was TT 0.87 (0.18) mm, MT 0.95 (0.34) mm and MM 0.88 (0.23) mm. There was no relation between the polymorphism and hypertension (TT 11 of 100 cases, six of 45 controls).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of association between angiotensinogen polymorphism (M235T) and cerebrovascular disease and carotid atheroma. 852 90

Genotypic abnormalities of the renin-ANG system have been suggested as a risk factor for the development of diabetic nephropathy. Cleavage of angiotensinogen is the rate-limiting step in the activation of the renin-ANG system. The TT genotype of a polymorphism encoding threonine instead of methionine (M235T) has been associated not only with increased plasma angiotensinogen concentration but also with essential hypertension. In addition, a polymorphism in the angiotensinogen gene substituting methionine for threonine (T174M) has been associated with hypertension in nondiabetic populations. We studied the relationship between these polymorphisms in the angiotensinogen gene in IDDM patients with diabetic nephropathy (121 men, 74 women, age 40.9 +/- 10 years, diabetes duration 27 +/- 8 years). There was no difference in M235T genotype distribution between IDDM patients with diabetic nephropathy and those with normoalbuminuria: 73/97/25 (37/50/13%) vs. 67/95/23 (36/52/12%) had MM/MT/TT genotypes, respectively. No difference in distribution of T174M genotypes between nephropathic and normoalbuminuric IDDM patients was observed either: 148/44/1 (77/23/0.5%) vs. 141/42/2 (76/23/1%) had TT/TM/MM genotypes, respectively. In patients with nephropathy, systolic blood pressure was higher (161 +/- 22 mmHg [mean +/- SD]) in patients carrying TT genotype of the M235T angiotensinogen polymorphism as compared with patients with MM or MT genotypes (150 +/- 23 mmHg; P = 0.03). We conclude that neither the M235T nor the T174M polymorphism in the angiotensinogen gene contributes to genetic susceptibility to diabetic nephropathy in white IDDM patients, whereas the TT genotype of the M235T is associated with elevated blood pressure in patients with diabetic nephropathy.
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PMID:Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy. 859 44

The allele 235T (a threonine in place of a methionine at position 235) of angiotensinogen has been found to be associated with a predisposition to essential hypertension. We investigated whether this allele also confers increased susceptibility to nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). A group of 380 patients who had had IDDM for 15 to 20 years were genotyped at the angiotensinogen 235 locus. Included were 75 patients with normoalbuminuria (albumin excretion rate < 30 micrograms/min), two series of patients with microalbuminuria (n = 30 and n = 136), and two series with overt proteinuria (n = 41 and n = 98). Allele 235T frequency was higher among cases with microalbuminuria (0.41 in the two series combined) or overt proteinuria (0.40) than in the normoalbuminuria group (0.36). However, this difference was not statistically significant with this sample size (chi 2 = 1.2, P = NS with 2 df). Under a recessive model, allele 235T homozygotes had a 1.6-fold risk of developing nephropathy relative to carriers of other genotypes, but this value was not significantly different from 1(95% CI = 0.8 to 3.5). The strength of the association did not improve after stratification by degree of glycemic control. With respect to the hypertension in these IDDM patients, no association with allele 235T was found. Allele 235T frequencies in normotensive and hypertensive individuals were 0.363 and 0.353, respectively, among normoalbuminuric IDDM individuals (chi 2 = 0.01, P = NS) and 0.411 and 0.414 among microalbuminuric IDDM subjects (chi 2 = 0.0, P = NS). We conclude that the angiotensinogen polymorphism M235T might influence susceptibility to nephropathy in insulin-dependent diabetes, but its effect, if any, is rather small and independent of hypertension.
Hypertension 1996 May
PMID:Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes. 862 Dec 7

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.
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PMID:Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. 882 46

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.
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PMID:Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM. 887 96

The angiotensinogen gene locus (1q42-43) has been linked to hypertension in affected relative-pair studies (including a previous UK study), but the role of the Met-->Thr polymorphism at position 235 remains controversial. Using this marker, we investigated the relationship between angiotensinogen genotype and blood pressure in two data sets from the East Anglia region of the United Kingdom. Two hundred twenty-three untreated hypertensive and 187 normotensive control subjects were recruited through local general practices. Blood pressure (including pretreatment measurements in the hypertensive group), age, sex, body mass index, alcohol consumption, cholesterol level, and angiotensinogen genotype were recorded for all subjects. The influence of angiotensinogen genotype on blood pressure was assessed with a general linear model ANOVA with adjustment for age, sex, body mass index, and alcohol consumption. There was no evidence for an association between angiotensinogen genotype and blood pressure level in either the hypertensive or normotensive data set. Angiotensinogen genotype did not influence blood pressure in subjects aged < 50 years, women, or those with a body mass index < 26 kg/m2. We conclude that the angiotensinogen Met-->Thr polymorphism is not a marker for blood pressure level in these East Anglian subjects. Further studies are required to confirm the involvement of the 1q locus in the development of hypertension in UK subjects and to delineate the functional variant(s) in this chromosomal region that influences blood pressure.
Hypertension 1996 Nov
PMID:Blood pressure and the M235T polymorphism of the angiotensinogen gene. 890 43


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