Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With the expression cloning of the subunits of the epithelial sodium channel, a new era has evolved in our basic understanding of the low-renin forms of human hypertension. The monogenic hypertensive syndromes manifest dysregulation of the epithelial sodium channel in the cortical collecting tubule. These rare syndromes provide a schema for organizing our thinking about the more common form(s) of low renin hypertension, and raise the possibility that dysregulation of sodium channel activity and consequent salt retention and volume expansion provide a basic pathophysiological mechanism for low-renin hypertension. What are needed are more specific agents to interrupt the mineralocorticoid response pathways, and clinically relevant approaches to measuring sodium channel activity at the level of the collecting tubule in the individual patient. The combined use of aldosterone antagonists and angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists could have a beneficial effect on "progression" of renal disease associated with glomerular and interstitial fibrosis, especially if the effects of hyperkalemia on the heart and aldosterone secretion can be minimized.
...
PMID:Low renin hypertension in the next millennium. 1065 Dec 17

The role of the endothelin-B receptor (ET(B)) in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. Spotting lethal (sl) rats carry a naturally occurring deletion in the ET(B) gene that completely abrogates functional receptor expression. Rats homozygous for this mutation die shortly after birth due to congenital distal intestinal aganglionosis. Genetic rescue of ET(B)(sl/sl) rats from this developmental defect using a dopamine--hydroxylase (DBH)-ET(B) transgene results in ET(B)-deficient adult rats. On a sodium-deficient diet, DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats both exhibit a normal arterial blood pressure, but on a high-sodium diet, the former are severely hypertensive. We find no difference in plasma renin activity or plasma aldosterone concentration between salt-fed wild-type, DBH-ET(B);ET(B)(+/+) or DBH-ET(B);ET(B)(sl/sl) rats, and acute responses to intravenous L-NAME and indomethacin are similar between DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats. Irrespective of diet, DBH-ET(B);ET(B)(sl/sl) rats exhibit increased circulating ET-1, and, on a high-sodium diet, they show increased but incomplete hypotensive responses to acute treatment an ET(A)-antagonist. Normal pressure is restored in salt-fed DBH-ET(B);ET(B)(sl/sl) rats when the epithelial sodium channel is blocked with amiloride. We conclude that DBH-ET(B);ET(B)(sl/sl) rats are a novel single-locus genetic model of severe salt-sensitive hypertension. Our results suggest that DBH-ET(B);ET(B)(sl/sl) rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.
...
PMID:Salt-sensitive hypertension in endothelin-B receptor-deficient rats. 1074 72

More than 50 million Americans display blood pressures outside the safe physiological range. Unfortunately for most individuals, the molecular basis of hypertension is unknown, in part because pathological elevations of blood pressure are the result of abnormal expression of multiple genes. This review identifies a number of important blood pressure regulatory genes including their loci in the human, mouse, and rat genome. Phenotypes of gene deletions and overexpression in mice are summarized. More detailed discussion of selected gene products follows, beginning with proteins involved in ion transport, specifically the epithelial sodium channel and sodium proton exchangers. Next, proteins involved in vasodilation/natriuresis are discussed with emphasis on natriuretic peptides, guanylin/uroguanylin, and nitric oxide. The renin angiotensin aldosterone system has an important role antagonizing the vasodilatory cyclic GMP system.
...
PMID:The molecular basis of hypertension. 1087 46

Our basic understanding of Na(+) transport mechanisms provides unique insights into epithelial transport processes. Unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect Na(+) balance, resulting in both N(a+) retaining and Na(+) wasting conditions. A major focus has been the epithelial sodium channel (ENaC), which can be activated by mutations (eg, Liddle's syndrome), changes in the response to mineralocorticoids (apparent mineralocorticoid excess syndrome), or production of mineralocorticoids (glucocorticoid-remediable aldosteronism). As a result, we now have clearly defined Mendelian syndromes in which ENaC activity is "dysregulated." This dysregulation leads to systemic hypertension associated with suppressed plasma renin activity, which can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low-renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension.
...
PMID:Aldosterone-related genetic effects in hypertension. 1098 Nov 63

The general intake of salt (sodium chloride) is much higher than the recommended allowances, in part because of added salt in food industry processed food. However, population studies have not been able to show an association between salt intake and unfavorable health outcome. Based on population studies and randomized studies, the effect of an extreme salt reduction of 100 mmol on blood pressure in hypertensive persons is about one third of the effect of antihypertensive medications. This effect-size estimate is based on single measurements of blood pressure and is probably overestimated compared with 24-hour blood pressure measurements. Salt reduction has effects on heart rate and serum levels of renin, aldosterone, catecholamines, and lipids that may be unfavorable. Because of insufficient compliance, extreme salt reduction can only be obtained if salt in food industry processed food is eliminated. The full consequences of such elimination are not known. Other nonpharmacological interventions, such as weight reduction and diets including fruits, vegetables, and low-fat dairy foods, are probably easier to implement and more effective to decrease blood pressure than salt reduction. Furthermore, salt reduction does not seem to add to the effect size when combined with other nonpharmacological interventions. Salt sensitivity due to sodium channel mutations has been shown in a minority of blacks but not in Caucasians. In conclusion, at present, dietary salt restriction should not be a basic component of antihypertensive therapy.
...
PMID:Should dietary salt restriction be a basic component of antihypertensive therapy? 1099 44

Recent advances in genetic determination of human essential hypertension (EHT) are discussed by reviewing the candidate genes. Candidate genes have been selected based on genetic information from classical linkage analysis (affected sib-pair analysis) or mendelian hypertension (autosomal dominant inheritance of hypertension). Most of these genes are, directly or indirectly, coupled to salt handling of the kidney, being included in the renin-angiotensin system (RAS), steroid-hormone metabolism, and renal sodium transporters. Angiotensinogen (AGT) gene in RAS was first described as a strong candidate associated with the onset of hypertension, since sib-pair linkage analysis has demonstrated the trait loci for hypertension which includes the coding region for AGT. M235T polymorphism of AGT has been studied extensively in many populations including Japanese, and the results suggest a weak, but significant linkage with hypertension. The presence (insertion [I]) or absence (deletion [D]) of 287bp in intron 16 of angiotensin converting enzyme gene has also been examined in RAS, and the results suggest D polymorphism as a risk factor for hypertension in men. Other components in RAS, such as renin, angiotensinogen II type I receptor, or kallikrein have also been studied, but the available information is still incomplete. Genetic investigations of mendelian hypertension has identified the genetic mechanisms for glucocorticoid remediable aldosteronism, apparent mineral corticoid excess, and Liddle's syndrome as chimeric gene duplications of CYP11B1 (aldosterone synthase gene) and CYP11B2 (11beta-hydroxylase gene), mutations in the gene of 11beta-hydroxysteroid dehydrogenase type 2 that catalyzes the conversion of cortisol to cortisone, and mutations in beta or gamma subunit of epithelial sodium channel (ENaC), respectively. Subsequently, genetic variants of CYP11B2 and beta or gamma subunit of ENaC have been found, suggesting the -344C polymorphism of CYP11B2, 594S variant of betaENaC, and two rare variants of gammaENaC as risk factors for EHT. In spite of the extensive research, haplotypes in individual populations remain to be elucidcated in most candidate genes. Even casual conclusions of possible linkage with EHT need to be further examined with better determinations of phenotypes, such as ambulatory and home blood pressure monitoring or identification of onset of hypertension in cohort studies.
...
PMID:Genetic determination of human essential hypertension. 1112 65

Plasma renin activity is significantly lower in black people compared with whites independent of age and blood pressure status. The lower PRA appears to be due to a reduction in the rate of secretion of renin but the exact mechanistic events underlying such differences in renin release between blacks and whites are still not fully understood. Nevertheless, given the paramount importance of the renin-angiotensin system in the control of sodium balance, a most likely explanation is that the lower renin is a consequence of differences in renal sodium handling between blacks and whites. The lower PRA does not reflect differences in dietary sodium intake but the evidence available suggests that the low PRA could be part of the corrective mechanisms designed to maintain sodium balance in the presence of an increased tendency for sodium retention in black people. While it is possible that several factors may contribute to the reduced PRA, more recent investigation at the molecular level suggests that the lower PRA may arise from gene variation in the renal epithelial sodium channel. The functional significance of the lower PRA in relation to the different pattern of cardiovascular and renal disease between blacks and whites remains unclear. Moreover, direct investigations of pre-treatment renin status in hypertensive blacks in relation to blood pressure response have demonstrated that the pre-treatment PRA is not a good index of subsequent blood pressure response to pharmacological treatment. Nevertheless, the blood pressure reduction to short term sodium restriction is greater in blacks compared with whites and, in the black subjects, the greater reduction in blood pressure to sodium restriction appears to be related, at least in part, to the decreased responsiveness of the renin-angiotensin system. Journal of Human Hypertension (2001) 15, 17-25
...
PMID:Why is plasma renin activity lower in populations of African origin? 1122 98

Growth hormone (GH) treatment causes salt and water retention, and this effect has been suggested to be mediated by activation of epithelial sodium channel (ENaC). Multi-system pseudohypoaldosteronism (PHA) is a salt wasting disease resulting from mutations in ENaC subunit genes. We examined effects of GH therapy for 12-21 months on the renin-angiotensin-aldosterone system (RAAS) in 12 children with idiopathic short stature (ISS) and a PHA patient with defective ENaC function and concomitant GH deficiency. On GH therapy (0.7 U/kg/week), plasma renin activity (PRA), serum aldosterone and insulin-like growth factor-I (IGF-I) levels were periodically determined every 1-3 months in all children. The PHA patient was studied for 6 yr during which time serum, urine, and sweat electrolytes and secretion rate were also examined before, on and off GH therapy. In the PHA patient, mean plasma aldosterone concentration, 7.7 nmol/l (278 ng/dl) before therapy (n=9) rose to 73 nmol/l (2650 ng/dl) 10 months after GH. PRA and IGF-I increased similarly, reaching a plateau between 8 and 12 months. Off GH, there was a decrease to pretreatment levels in 30 months. Aldosterone and PRA strongly correlated with IGF-I (r=0.66 and 0.67). GH therapy also improved the growth rate, and increased both sweat secretion rate and Na(+)/K(+) ratio. In children with ISS, aldosterone and IGF-I peaked 6-12 months after GH. Off GH their levels normalized in 3 months. These findings indicate that long-term GH activates the RAAS in both children with ISS and a PHA patient, and that this effect does not depend on a fully functional ENaC.
...
PMID:Growth hormone activates renin-aldosterone system in children with idiopathic short stature and in a pseudohypoaldosteronism patient with a mutation in epithelial sodium channel alpha subunit. 1135 74

Our basic understanding of sodium mechanisms provides unique insights into epithelial transport processes, and unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect sodium balance, with both sodium-retaining and sodium-wasting conditions being the consequence. A major focus of such studies has been the epithelial sodium channel, which can be activated by mutations in the channel subunits or mineralocorticoid receptor, and changes in the response to or production of mineralocorticoids. As a result, there are now clearly defined Mendelian syndromes in which epithelial sodium channel activity is 'dysregulated', with the subsequent development of systemic hypertension with suppressed plasma renin activity that can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension, and more clearly define the interactions of dietary constituents such as sodium and potassium in the regulation of blood pressure.
...
PMID:Genetic forms of human hypertension. 1145 30

It remains to be defined whether molecular variants of the genes underlying Mendelian forms of hypertension play some etiological role in essential hypertension. To pursue this issue, we focused on the following three genes: the epithelial sodium channel (ENaC), 11beta-hydroxysteroid dehydrogenase type 2, and mineralocorticoid receptor genes. Five sequence variations of these genes, which were either previously reported to show significant association with hypertension or identified as "mild" molecular variants, were chosen for our study. Each variation was screened in 247 severe hypertensive patients with early onset (<45 years) and any detectable variations were subsequently characterized in 291 older normotensive subjects (>60 years) for the case-control comparison. We also investigated the significance of association between the tested variants and biochemical parameters reflecting sodium-water homeostasis, such as plasma aldosterone concentration (PAC) and renin activity (PRA). Only the T663A variant (alpha-subunit of ENaC) turned out to be polymorphic in the Japanese population. In disagreement with positive associations previously reported in white and black subjects, we observed no significant association between T663A and hypertension, while allele frequencies of A663 were higher in Japanese (58-64%) compared with a reported prevalence of 29% in whites and 15% in blacks. T663A showed a borderline association (p=0.02) with the PAC/PRA ratio but not with PAC or PRA in the multivariate analysis. Our data did not support the association between Mendelian disease gene variants and essential hypertension in the Japanese. However, the present study did not definitively resolve this issue and further investigation is certainly warranted.
...
PMID:Evaluation of selected polymorphisms of the Mendelian hypertensive disease genes in the Japanese population. 1167 45


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---