Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MicroRNAs (miRNAs) comprise a post-transcriptional layer of gene regulation shown to be involved in diverse physiological processes. We aimed to study whether regulatory networks that determine susceptibility to hypertension may involve a miRNA component. Screening of loci, involved in renal water-salt balance regulation, highlighted the mineralocorticoid receptor gene NR3C2 as a potential target for several miRNAs. A luciferase assay demonstrated that miR-124 and miR-135a suppress NR3C2 3'UTR reporter construct activity 1.5- and 2.2-fold, respectively. As the tested miRNAs did not reduce the levels of target mRNA, we suggest that the binding of miR-124 and miR-135a to NR3C2 3'UTR contributes to the translational, not transcriptional regulation of the gene. Co-expression of two different miRNAs did not increase the repression of the reporter gene, indicating no additive or synergistic effects between the tested miRNAs. Our results demonstrate that by repressing the mineralocorticoid receptor gene NR3C2, miR-124 and miR-135a could participate in the regulation of renin-angiotensin-aldosterone system and thereby might be involved in blood pressure regulation.
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PMID:MicroRNAs miR-124 and miR-135a are potential regulators of the mineralocorticoid receptor gene (NR3C2) expression. 1994 75

AIMS. Blood pressure control is influenced by various genetic and environmental factors, and genetic susceptibility is important in the development of essential hypertension. Because the renin-angiotensin-aldosterone system (RAAS) has a key role in vasoconstriction, vasodilation, and sodium and electrolyte balance, it is central in blood pressure control and so is an appropriate target in hypertension treatments. The present study assessed the association of RAAS-related genes with blood pressure and hypertension in a Korean population. Single nucleotide polymorphisms (SNPs, n = 114) in nine RAAS-related genes (AGT, REN, ACE, ACE2, AGTR1, CYP11B2, NR3C2, MAS1, and CMA1) were assessed for their correlation with blood pressure and hypertension using genotype data of 8842 individuals from the Korea Association Resource subject pool. MAJOR FINDINGS. Linear regression analysis revealed a statistically significant association with blood pressure of 10 SNPs in six genes (ACE, ACE2, CYP11B2, NR3C2, MAS1, and CMA1). An additional hypertension case-control study identified 10 SNPs in NR3C2 and ACE that were linked to hypertension. PRINCIPAL CONCLUSION. Three SNPs (rs11737660, rs6810951, and rs10519963) in NR3C2 correlate with both blood pressure and hypertension. Genetic polymorphisms in RAAS-related genes appear to be associated with hypertension in a Korean population.
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PMID:Association between renin-angiotensin-aldosterone system-related genes and blood pressure in a Korean population. 2134 26

There is evidence that uncontrolled arterial hypertension (AHT) in patients with metabolic syndrome (MS) increases cardiovascular risks. The renin-angiotensin-aldosterone system (RAAS) and its polymorphisms apparently confer a genetic risk for uncontrolled AHT. This study aims to investigate the influence of RAAS polymorphisms on AHT control in patients diagnosed with MS. This is a two-stage population-based nested case-control pilot study (n=1514). We differentiated between MS-diagnosed patients and non-MS patients (ATP-III criteria) and selected those individuals diagnosed with AHT from each group (n=161 and n=156, respectively). Those who successfully controlled their AHT (controls) and those who did not were compared. In the MS population, the C/G and G/G genotypes of single-nucleotide polymorphism rs1040288 (NR3C2) and A/G and G/G of rs11099680 (NR3C2) were associated with uncontrolled AHT (odds ratio (OR)=2.94 (1.34-6.47) and OR=2.54 (1.09-5.93), respectively). According to Akaike's information criteria, the best adjusted model included gender and age as confounding variables (adjusted OR (ORa)=2.91 (1.31-6.46) and ORa=2.67 (1.13-6.31), respectively). Regarding rs1040288, an ORa of 4.03 (1.44-11.26) was obtained for the saturated model (adjusted for gender, age, waist-to-hip ratio, body mass index, biochemical profile, renal damage, smoking habit and anti-AHT treatment). Yet, when the same analysis was performed on the non-MS population, no association was found between rs11099680 and the failure to control AHT. The results reveal a possible association between the rs11099680 RAAS polymorphism and uncontrolled AHT in MS-diagnosed patients. rs1040288 appears to be associated with uncontrolled blood pressure regardless of MS profile.
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PMID:Inefficient arterial hypertension control in patients with metabolic syndrome and its link to renin-angiotensin-aldosterone system polymorphisms. 2147 72

Pseudohypoaldosteronism type 1 (PHA1) is a rare form of mineralocorticoid resistance characterized in newborns by salt wasting with dehydration, hyperkalemia and failure to thrive. This disease is heterogeneous in etiology and includes autosomal dominant PHA1 owing to mutations of the NR3C2 gene encoding the mineralocorticoid receptor, autosomal recessive PHA1 due to mutations of the epithelial sodium channel (ENaC) gene, and secondary PHA1 associated with urinary tract diseases. Amongst these diseases, autosomal dominant PHA1 shows has manifestations restricted to renal tubules including a mild salt loss during infancy and that shows a gradual improvement with advancing age. Here, we report a neonatal case of PHA1 with a NR3C2 gene mutation (a heterozygous c.2146_2147insG in exon 5), in which the patient showed failure to thrive, hyponatremia, hyperkalemia, and elevated plasma renin and aldosterone levels. This is the first case of pseudohypoaldosteronism type 1 confirmed by genetic analysis in Korea.
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PMID:A case of pseudohypoaldosteronism type 1 with a mutation in the mineralocorticoid receptor gene. 2150 3

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.
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PMID:Structural chromosome disruption of the NR3C2 gene causing pseudohypoaldosteronism type 1 presenting in infancy. 2193 99

Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with elevated plasma aldosterone and renin levels. Two types of PHA1 have been described: an autosomal recessive systemic form and an autosomal dominant renal form, in which the target organ defect is confined to the renal tubules. The dominant renal form of PHA1 is caused by heterozygous mutations in the NR3C2 gene, which encodes the mineralocorticoid receptor (MR). We determined clinical and biochemical parameters in two familial and four sporadic Japanese patient and analyzed the status of the NR3C2 gene. Failure to thrive was noted in five of the six patients. In one of the familial cases, the mother had an episode of failure to thrive when she was a toddler, but received no medical treatment. NaCl supplementation was discontinued in four of the six patients after they reached one year of age and they have grown normally thereafter. However, in one patient, 9 g/day of salt has been required to maintain serum Na concentration after 1 year of age. Analysis of NR3C2 identified three novel mutations [c. C1951T (p.R651X), c.304_305delGC (p.A102fsX103), c.del 603A (p.T201fsX34)] and one previously reported mutation [c.A2839G (p.947X)]. p.R651X was identified in one familial case and one unrelated sporadic patient. The patient who has been supplemented with large amount of salt was heterozygous for c.del 603A in exon 2. In conclusion, our study expands the spectrum of phenotypes, and characterized mutations of NR3C2 in the renal form of PHA1.
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PMID:Clinical and molecular analysis of six Japanese patients with a renal form of pseudohypoaldosteronism type 1. 2319 15

Pseudohypoaldosteronism (PHA) is a rare syndrome of mineralocorticoid resistance. PHA type 1 (PHA1) can be divided into two different forms, showing either a systemic or a renal form of mineralocorticoid resistance. The first is caused by mutations of the genes coding the epithelial sodium channel, the latter is caused by mutations in the mineralocorticoid receptor coding gene NR3C2. The clinical manifestation of systemic PHA1 is overt dehydration and hyponatremia due to systemic salt loss and severe hyperkalemia. The leading clinical sign of the less severe renal PHA1 is insufficient weight gain due to chronic dehydration. Hyperkalemia is generally mild. The patients manifest clinical signs mainly in early infancy. In both entities, plasma renin and aldosterone concentrations are highly elevated, reflecting a resistance of the kidney and other tissues to mineralocorticoids. PHA2 is characterized by hyperkalemia and hypertension. It has been described by Gordon's group as a syndrome with highly variable plasma aldosterone concentrations, suppressed plasma renin activity, various degrees of hyperchloremia and metabolic acidosis. PHA3 comprises transient and secondary forms of salt-losing states caused by various pathologies. Urinary tract infections and obstructive uropathies are the most frequent cause. Contrary to PHA1 and PHA2, the glomerular filtration rate is decreased in PHA3.
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PMID:Pseudohypoaldosteronism. 2339 97

Numerous studies have demonstrated the interaction that exists between adipocyte differentiation, energy balance and factors involved in fluid and electrolyte homeostasis, such as the renin-angiotensin-aldosterone system. More specifically, a potential impact of aldosterone on the function of several organs implicated in the control of energy homeostasis, such as adipose tissue, liver, skeletal muscle or pancreas, has been recently described. In addition, the mineralocorticoid receptor (MR, NR3C2), a transcription factor, was shown to play a crucial role on white and brown adipocyte differentiation and function, mediating the effects of both mineralocorticoid and glucocorticoid hormones on adipose tissues. Transgenic mouse models as well as pharmacological inactivation of MR signaling provided compelling evidence that MR is an important control point for energy homeostasis. Herein, we review recent findings on the involvement of aldosterone but also of MR on energy metabolism and discuss the therapeutic potential of manipulating MR signaling for the management of metabolic disorders in humans.
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PMID:The mineralocorticoid receptor: a new player controlling energy homeostasis. 2543 33

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease characterized by resistance to aldosterone, and the renal form of PHA1 is associated with heterozygous inactivating mutations in NR3C2, which encodes mineralocorticoid receptor (MR). Here we report a case of renal PHA1 due to a novel frameshift mutation in NR3C2. A 10-day-old Japanese male infant, born at 39 weeks gestation (birth weight, 2,946 g), was admitted to our hospital because of lethargy and vomiting, with a 6.7% weight loss since birth. Laboratory test results were: Na+, 132 mEq/L; K+, 6.6 mEq/L; Cl+, 93 mEq/L. Both plasma aldosterone level and plasma renin activity were markedly elevated at diagnosis, 2,940 ng/dL (normal range: 26.9-75.8 ng/dL) and 560 ng/mL/h (normal range 3.66-12.05 ng/mL/h), respectively. Direct sequence analysis of NR3C2 revealed a novel heterozygous mutation (c.3252delC) in the patient and his father. The mutation causes a frameshift starting at amino acid I 963 within the C terminal ligand-binding domain of MR and results in a putative abnormal stop codon at amino acid 994, with an extension of 10 amino acids compared to normal MR. We performed cell culture experiments to determine the levels of mutant NR3C2 mRNA and MR, and evaluate the effects of the mutation on MR response to aldosterone. The mutation decreased the expression of MR, but not NR3C2 mRNA, and led to decreased MR function, with no dominant negative effect. These results provide important information about MR function and NR3C2 mutation in PHA1.
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PMID:A novel frameshift mutation in NR3C2 leads to decreased expression of mineralocorticoid receptor: a family with renal pseudohypoaldosteronism type 1. 2772 60

The existence of a local renin-angiotensin system (RAS) specific to the hematopoietic bone marrow (BM) microenvironment had been proposed two decades ago. Most of the RAS molecules including ACE, ACE2, AGT, AGTR1, AGTR2, AKR1C4, AKR1D1, ANPEP, ATP6AP2, CMA1, CPA3, CTSA, CTSD, CTSG, CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP21A2, DPP3, EGFR, ENPEP, GPER, HSD11B1, HSD11B2, IGF2R, KLK1, LNPEP, MAS1, MME, NR3C1, NR3C2, PREP, REN, RNPEP, and THOP1 are locally present in the BM microenvironment. Local BM RAS peptides control the hematopoietic niche, myelopoiesis, erythropoiesis, thrombopoiesis and the development of other cellular lineages. Local BM RAS is important in hematopoietic stem cell biology and microenvironment. Angiotensin II regulates the proliferation, differentiation, and engraftment of hematopoietic stem cells. Activation of Mas receptor or ACE2 promotes proliferation of CD34+ cells. BM contains a progenitor that expresses renin throughout development. Angiotensin II attenuates the migration and proliferation of CD34+ Cells and promotes the adhesion of both MNCs and CD34+ cells. Renin cells in hematopoietic organs are precursor B cells. The renin cell requires RBP-J to differentiate. Mutant renin-expressing hematopoietic precursors can cause leukemia. Deletion of RBP-J in the renin-expressing progenitors enriches the precursor B-cell gene programme. Mutant cells undergo a neoplastic transformation, and mice develop a highly penetrant B-cell leukemia with multi-organ infiltration and early death. Many biological conditions during the development and function of blood cells are mediated by RAS, such as apoptosis, cellular proliferation, intracellular signaling, mobilization, angiogenesis, and fibrosis. The aim of this paper is to review recent developments regarding the actions of local BM RAS in the genesis of leukemia and other malignancies molecules.
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PMID:Local bone marrow renin-angiotensin system in the genesis of leukemia and other malignancies. 2777 88


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