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)

Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (n=8); captopril alone (50 mg. kg-1. d-1, orally) (n=10); aldosterone infusion alone (40 microg. kg-1. d-1, SC) (n=7); or captopril and aldosterone at 20 (n=6) or 40 (n=7) microg. kg-1. d-1. Systolic blood pressure was markedly elevated in all groups. Vehicle- and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21+/-3% and 29+/-3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 microg. kg-1. d-1 in captopril-treated SHRSP resulted in the development of severe renal lesions (16+/-3% and 21+/-2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure.
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PMID:Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats. 993 Nov 10

Targeted disruption of mineralocorticoid receptor (MR) gene results in pseudohypoaldosteronism type I with failure to thrive, severe dehydration, hyperkalemia, hyponatremia, and high plasma levels of renin, angiotensin II, and aldosterone. In this study, mRNA expression of the different components of the renin-angiotensin system (RAS) were evaluated in liver, lung, heart, kidney and adrenal gland to assess their response to a state of extreme sodium depletion. Angiotensinogen, renin, angiotensin-I converting enzyme, and angiotensin II receptor (AT1 and AT2) mRNA expressions were determined by Northern blot and RT-PCR analysis. Furthermore, in situ hybridization and immunohistochemistry allowed us to identify the cell types involved in the variation of the RAS component expression. In the heterozygous mice (MR+/-), compared with wild-type mice (MR+/+), there was no significant variation of any mRNA of the RAS components. In MR knockout mice (MR-/-), compared with wild-type mice, there were significant increases in the expression level of several RAS components. In the liver, angiotensinogen and AT1 receptor mRNA expressions were moderately stimulated. In the kidney, renin mRNA was increased up to 10-fold and in situ hybridization showed a marked recruitment of renin-producing cells; however, the levels of angiotensin-I converting enzyme mRNA and AT1 mRNA were not changed. Interestingly, in adrenal gland, renin expression was also strongly up-regulated in a thickened zona glomerulosa, whereas AT1 mRNA expression remained unchanged. Altogether, these results demonstrate that in the MR knockout mice model, RAS component expressions are differentially altered, renin being the most stimulated component. Angiotensinogen and AT1 in the liver are also increased, but the other elements of the RAS are not affected.
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PMID:Effects of mineralocorticoid receptor gene disruption on the components of the renin-angiotensin system in 8-day-old mice. 997 59

In the general population blood pressure varies along a continuum and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Epidemiological studies suggest that blood pressure variance is attributable to both genetic factors and environmental factors to the same magnitude. The molecular basis for three forms of sever hypertension transmitted on an autosomal basis has been recently elucidated: a) the glucocorticoid-suppressible aldosteronism (GSA), b) the Liddle's syndrome and c) the syndrome of apparent mineralocorticoid excess (AME). GSA is due to expression of a chimeric gene produced by fusion of the 11 beta-hydroxylase promoter with the region encoding the enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of ACTH, and can be suppressed by administration of glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption, which can be suppressed by administration of amiloride or triamterene. AME is caused by mutations of the 11 beta-hydroxysteroid dehydrogenase type 2 enzyme, an enzyme that metabolises cortisol into its receptor inactive keto-form cortisone, thus protecting the mineralocorticoid receptor from occupation by glucocorticoids. Apart from these rare genetic defects of the extended renin-angiotensin system, there are many susceptibility genes that might increase the risk of hypertension in a given environment. Several studies have demonstrated a link between the angiotensinogen gene and familial hypertension. One variant of angiotensinogen gene is associated with elevated plasma angiotensinogen levels and is more prevalent among hypertensive than among normotensive. This observation shows the relationship between the angiotensinogen genotype, the intermediate phenotype (i.e., plasma angiotensinogen elevation), and the distant phenotype (i.e., blood pressure elevation). The identification of these genes as well as other informative genetic markers distributed along the genome could be used in the search for genetic links between arterial hypertension and a chromosomal locus.
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PMID:[Molecular genetics of hypertension in the human]. 1006 28

There is increasing evidence for important cardiovascular effects of aldosterone via classical mineralocorticoid receptors in the heart. Administration of aldosterone with excess salt produces both cardiac hypertrophy and interstitial cardiac fibrosis in rats, and concomitant administration of potassium canrenoate at a dose that only modestly lowers blood pressure completely blocks the cardiac effects of aldosterone. In the present study, we examined the effect on left ventricular hypertrophy of adding a low dose of the mineralocorticoid receptor antagonist spironolactone (25 mg/d) to an angiotensin-converting enzyme inhibitor (enalapril maleate) in patients with essential hypertension. Eighteen untreated patients with moderate to severe essential hypertension based on the WHO/ISH guidelines participated in this study. Subjects were treated with either an angiotensin-converting enzyme inhibitor alone (group I: 10 patients, 4 men and 6 women, mean age 56 +/- 18 yr) or an angiotensin-converting enzyme inhibitor plus spironolactone (group II: 8 patients, 3 men and 5 women, mean age 59 +/- 14 yr) for 9 mo. Left ventricular mass index, various echocardiographic variables, mean blood pressure, plasma renin activity, and plasma aldosterone concentration before treatment were similar in the two groups. Blood pressure of both groups decreased significantly and similarly after antihypertensive treatment (group I, 136 +/- 9/82 +/- 9 mmHg; group II, 133 +/- 9/85 +/- 10 mmHg). Left ventricular mass index also decreased significantly in both groups (group I, -10.2 +/- 7.1%; group II, -18.1 +/- 6.9%). The extent of reduction was significantly greater in the spironolactone group (group II) (p < 0.05 vs. group I). In group II patients, spironolactone did not cause any side effects during the observation period. We conclude that spironolactone may have beneficial effects on left ventricular hypertrophy in patients with essential hypertension who are receiving an angiotensin-converting enzyme inhibitor.
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PMID:Effects of spironolactone and angiotensin-converting enzyme inhibitor on left ventricular hypertrophy in patients with essential hypertension. 1022 46

Brain mineralocorticoid receptors appear to contribute to mineralocorticoid hypertension and may be involved in blood pressure control in normotensive rats. We examined the effect of blockade of central mineralocorticoid receptors with the use of a selective antagonist (RU28318) on cardiovascular and renal function in conscious normotensive rats. The contribution of renal innervation was evaluated in rats with bilaterally denervated kidneys. Young adult, male Wistar rats were trained for systolic blood pressure measurement by a tail sphygmographic method and accustomed to metabolic cages for collection of urine. One week before experimentation, an intracerebroventricular cannula was implanted. Systolic blood pressure was diminished 30 minutes after an intracerebroventricular dose of 10 ng of RU28318. The effect was maximal at 8 hours and was still present after 24 hours. Blood pressure returned to the basal level by 48 hours. During the period 0 to 8 hours after intracerebroventricular injection, rats treated with the antagonist showed an increase in diuresis and urinary electrolyte excretion. No significant effect on plasma renin activity, measured 8 and 30 hours after administration of RU28318, was observed. In denervated rats, the decrease in systolic blood pressure after administration of RU28318 was reduced. The difference was statistically significant compared with controls at 2 hours but not at 8 hours, and blood pressure returned to the basal value by 24 hours. The increases in diuresis and urinary electrolyte excretion induced by RU28318 were abolished in denervated rats. These results show that brain mineralocorticoid receptors are involved in blood pressure regulation and kidney function homeostasis in conscious normotensive rats. The renal nerves appear to participate in the brain mineralocorticoid receptor control of blood pressure.
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PMID:Brain mineralocorticoid receptor control of blood pressure and kidney function in normotensive rats. 1033 12

The mineralocorticoid receptor knock-out mouse (MR-/-), resembling inborn pseudohypoaldosteronism, dies 8-12 days after birth in circulatory failure with all the signs of terminal volume contraction. The present study aimed to examine the functional defects in the kidney and colon in detail and to attempt to rescue these mice. In neonatal (nn) MR-/- the amiloride-sensitive short-circuit current in the colon was reduced to approximately one-third compared to controls (MR+/+ and MR+/-). In isolated in vitro perfused collecting ducts the amiloride-induced hyperpolarization of the basolateral membrane (Vbl) of nn MR-/- was similar to that of controls, but urinary Na+ excretion was markedly increased to 4.3 micromol/day.g (BW). Based on this measured urinary Na+ loss we tried to rescue nn MR-/- mice by injecting NaCl twice daily (3.85 micromol/g BW), corresponding to 22 microliter of isotonic saline/g BW subcutaneously. This regimen was continued until the animals had reached a body mass of 8.5 g. Thereafter, in addition to normal chow and tap water, NaCl drinking water (333 mmol/l) and pellets soaked in 333 mmol/l NaCl were offered. Unlike the untreated nn MR-/- most of these mice survived. The adult animals were examined between days 27 and 41, some were used for breeding. When compared to age-matched controls the growth of MR-/- was delayed until day 20. Then their growth curve increased in slope and reached that of controls. MR-/- retained their Na+-losing defect. Amiloride's effect on urinary Na+ excretion was not significant in MR-/- mice and the effect on Vbl in isolated cortical collecting ducts was attenuated. The renin-producing cells were hypertrophic and hyperplastic. Plasma renin and aldosterone concentrations were significantly elevated in MR-/- mice. These data indicate that MR-/- can be rescued by timely and matched NaCl substitutions. This enables the animals to develop through a critical phase of life, after which they adapt their oral salt and water intake to match the elevated excretion rate; however, the renal salt-losing defect persists.
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PMID:Rescue of the mineralocorticoid receptor knock-out mouse. 1039 52

Local tissue concentrations of glucocorticoids are modulated by the enzyme 11beta-hydroxysteroid dehydrogenase which interconverts cortisol and the inactive glucocorticoid cortisone in man, and corticosterone and 11-dehydrocorticosterone in rodents. The type I isoform (11beta-HSD1) is a bidirectional enzyme but acts predominantly as a oxidoreductase to form the active glucocorticoids cortisol or corticosterone, while the type II enzyme (11beta-HSD2) acts unidirectionally producing inactive 11-keto metabolites. There are no known clinical conditions associated with 11beta-HSD1 deficiency, but gene deletion experiments in the mouse indicate that this enzyme is important both for the maintenance of normal serum glucocorticoid levels, and in the activation of key hepatic gluconeogenic enzymes. Other important sites of action include omental fat, the ovary, brain and vasculature. Congenital defects in the 11beta-HSD2 enzyme have been shown to account for the syndrome of apparent mineralocorticoid excess (AME), a low renin severe form of hypertension resulting from the overstimulation of the non-selective mineralocorticoid receptor by cortisol in the distal tubule of the kidney. Inactivation of the 11beta-HSD2 gene in mice results in a phenotype with similar features to AME. In addition, these mice show high neonatal mortality associated with marked colonic distention, and remarkable hypertrophy and hyperplasia of the distal tubule epithelia. 11Beta-HSD2 also plays an important role in decreasing the exposure of the fetus to the high levels of maternal glucocorticoids. Recent work suggests a role for 11beta-HSD2 in non-mineralocorticoid target tissues where it would modulate glucocorticoid access to the glucocorticoid receptor, in invasive breast cancer and as a mechanism providing ligand for the putative 11-dehydrocorticosterone receptor. While previous homologies between members of the SCAD superfamily have been of the order of 20-30% phylogenetic analysis of a new branch of retinol dehydrogenases indicates identities of > 60% and overlapping substrate specificities. The availability of crystal structures of family members has allowed the mapping of conserved 11beta-HSD domains A-D to a cleft in the protein structure (cofactor binding domain), two parallel beta-sheets, and an alpha-helix (active site), respectively.
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PMID:The type I and type II 11beta-hydroxysteroid dehydrogenase enzymes. 1041 17

The monogenic forms of human hypertension have yielded to the power of modern genetic techniques in the last several years. With the successful expression cloning of the subunits of the epithelial sodium channel, a whole era has evolved in our basic understanding of the low renin forms of human hypertension. Of note, all of these hypertensive syndromes (Liddle's syndrome, glucocorticoid-remediable aldosteronism, and the apparent mineralocorticoid excess syndrome) share an underlying dysregulation of the activity of the epithelial sodium channel in the cortical collecting tubule. Loss of function defects due to mutations in the channel subunits themselves, or in the mineralocorticoid receptor (pseudohypoaldosteronism, type I) also affect blood pressure regulation consequent to renal salt wasting and dysregulation of the epithelial sodium channel in the cortical collecting tubule.
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PMID:Hypertension. 1043 75

Recent data suggest an interaction between the renin-angiotensin-aldosterone system and fibrinolysis. Although previous work has focused on the effect of angiotensin II (Ang II) on plasminogen activator inhibitor (PAI-1) expression, the present study tests the hypothesis that aldosterone contributes to the regulation of PAI-1 expression. To test this hypothesis in vitro, luciferase reporter constructs containing the human PAI-1 promoter were transfected into rat aortic smooth muscle cells. Exposure of the cells to 100 nmol/L Ang II resulted in a 3-fold increase in luciferase activity. Neither 1 micromol/L dexamethasone nor 1 micromol/L aldosterone alone increased PAI-1 expression. However, both dexamethasone and aldosterone enhanced the effect of Ang II in a dose-dependent manner. This effect was abolished by mutation in the region of a putative glucocorticoid-responsive element. A similar interactive effect of Ang II and aldosterone was observed in cultured human umbilical vein endothelial cells. The time course of the effect of aldosterone on Ang II-induced PAI-1 expression was consistent with a classical mineralocorticoid receptor mechanism, and the effect of aldosterone on PAI-1 synthesis was attenuated by spironolactone. To determine whether aldosterone affected PAI-1 expression in vivo, we measured local venous PAI-1 antigen concentrations in six patients with primary hyperaldosteronism undergoing selective adrenal vein sampling. PAI-1 antigen, but not tissue plasminogen activator antigen, concentrations were significantly higher in adrenal venous blood than in peripheral venous blood. Taken together, these data support the hypothesis that aldosterone modulates the effect of Ang II on PAI-1 expression in vitro and in vivo in humans.
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PMID:Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. 1063 8

The 11 beta-hydroxysteroid dehydrogenase type 2 (11 PHSD2) enzyme inactivates 11 betahydroxy steroids in sodium-transporting epithelia such as the kidney, thus protecting the non-selective mineralocorticoid receptor (MR) from occupation by cortisol in humans. Inhibition by xenobiotics such as liquorice or mutations in the HSD11 B2 gene, as occur in the rare monogenic hypertensive syndrome of apparent mineralocorticoid excess (AME), result in a compromised 11 betaHSD2 enzyme activity, which in turn leads to overstimulation of the MR by cortisol, sodium retention, hypokalaemia, low plasma renin and aldosterone concentrations, and hypertension. Whereas the first patients described with AME had a severe form of hypertension and metabolic derangements, with an increased urinary ratio of cortisol (THF+5alphaTHF) to cortisone (THE) metabolites, more subtle effects of mild 11 beta HSD2 deficiency on blood pressure have recently been observed. Hypertension with no other characteristic signs of AME was found in the heterozygous father of a child with AME, and we described a girl with a homozygous gene mutation resulting in only a slightly reduced 11 beta HSD2 activity causing 'essential' hypertension. Thus, depending on the degree of loss of enzyme activity, 11 beta HSD2 mutations can cause a spectrum of phenotypes ranging from severe, life-threatening hypertension in infancy to a milder form of the disease in adults. Patients with essential hypertension usually do not have overt signs of mineralocorticoid excess, but nevertheless show a positive correlation between blood pressure and serum sodium levels, or a negative correlation with potassium concentrations, suggesting a mineralocorticoid influence. Recent studies revealed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites in some patients with essential hypertension. These abnormalities may be genetically determined. A genetic association of a HSD11 B2 flanking microsatellite and hypertension in black patients with end-stage renal disease has been reported. A recent analysis of a CA-repeat allele polymorphism in unselected patients with essential hypertension did not find a correlation between this marker and blood pressure. Since steroid hormones with mineralocorticoid action modulate renal sodium retention, one might hypothesize that genetic impairment of 11 beta HSD2 activity would be more prevalent in salt-sensitive as compared with salt-resistant subjects. Accordingly, we found a significant association between the polymorphic CA-microsatellite marker and salt-sensitivity. Moreover, the mean ratio of urinary cortisol to cortisone metabolites, as a measure for 11betaHSD2 activity, was markedly elevated in salt-sensitive subjects. These findings suggest that variants of the HSD11 B2 gene may contribute to the enhanced blood pressure response to salt in some humans.
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PMID:The role of the 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension. 1093 Jan 96


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