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

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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)

We examined whether amiloride, an agent that possesses epithelial sodium channel (ENaC)- and sodium/hydrogen exchange (NHE)-inhibitory activities, would exhibit renal vascular protection in saline-drinking, stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP received amiloride (1.0 mg.kg(-1).day(-1), n = 6) or deionized water (3 mg.kg(-1).day(-1), n = 6) for 5 wk starting at 61 days of age. Systolic blood pressure (SBP) did not differ among the groups, and there was no difference in the average daily urine output, sodium excretion, or potassium excretion. Terminal urinary protein excretion, blood urea nitrogen, and renal thrombotic microangiopathic lesions were markedly reduced in the amiloride group with no difference in plasma renin activity (PRA). In a survival protocol, SHRSP infused subcutaneously with benzamil (0.7 mg.kg(-1).day(-1), n = 8), a selective ENaC inhibitor, dimethylamiloride (0.7 mg.kg(-1).day(-1), n = 8), a selective NHE inhibitor, or vehicle (n = 7) had comparable SBP. Dimethylamiloride nonetheless prolonged survival of SHRSP (P < 0.005 vs. vehicle), and benzamil-treated SHRSP lived even longer (P < 0.0001 vs. vehicle; P < 0.05 vs. dimethylamiloride). In a separate series, plasma potassium concentration was elevated by dimethylamiloride (3.4 +/- 0.1 meq/l, n = 8) and benzamil (3.3 +/- 0.1 meq/l, n = 8) relative to vehicle (3.0 +/- 0.1 meq/l, n = 8) at 4 but not at 24 h after dosing. These findings suggest the involvement of a sodium transport mechanism in the development of thrombotic microangiopathy in SHRSP, unrelated to marked changes in arterial pressure, PRA, plasma potassium, or urinary water and electrolyte excretion.
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PMID:Sodium transport antagonism reduces thrombotic microangiopathy in stroke-prone spontaneously hypertensive rats. 1498 15

Liddle's syndrome is an autosomal dominant disease characterized by sodium-sensitive early hypertension and mutations in either the beta- or gamma-subunit of the amiloride-sensitive epithelial sodium channel encoded by SCNN1B and SCNN1G. We sequenced the 381 bp-coding regions in exon 13 of SCNN1B and the 381 bp-coding regions in exon 12 of SCNN1G in 948 and 953 Japanese patients with hypertension, respectively. In the SCNN1B gene, we identified three missense mutations, P592S (n=3), T594M (n=2), and E632K (n=1) in a heterozygous state in addition to four synonymous ones, Ile515 (n=1), Ser520 (n=19), Ser533 (n=1), and Thr594 (n=11). In the SCNN1G gene, we identified three missense mutations, A578V (n=1), P603S (n=1), and L609F (n=1) in a heterozygous state in addition to two synonymous ones, Ile550 (n=1) and Leu649 (n= 91, heterozygous; n=2, homozygous). We did not identify the same mutations previously reported in Liddle's syndrome kindreds. Two of the six hypertensive patients with missense mutation in the SCNN1B gene showed atypical renin and aldosterone levels, though one of them was diagnosed with renovascular hypertension. One patient with T594M in the SCNN1B gene was resistant to hypertension. The roles of these missense mutations in the SCNN1B or SCNN1G gene identified in hypertensive patients are not clear in the pathogenesis of hypertension and the regulation of electrolytes. Thus, further investigation of these mutations, including functional analyses, will be needed.
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PMID:Six missense mutations of the epithelial sodium channel beta and gamma subunits in Japanese hypertensives. 1519 80

Dietary fructose, NaCl, and/or saturated fat have been correlated with mean arterial pressure (MAP) rises in sensitive strains of rats. Dysregulation of sodium and/or water reabsorption by the kidney may contribute. Using radiotelemetry and parallel semiquantitative immunoblotting, we examined the effects of various diets on MAP and the regulation of abundance of the major renal sodium and water transport proteins in male Sprague-Dawley rats. In study 1, rats ( approximately 275 g) were fed one of four diets for 4 wk (n = 6/group): 1) control, 2) 65% fructose, 3) control + added NaCl (2.59%), or 4) fructose + NaCl. In study 2, 5% butter (fat) was added to the above four diets. Both fat and NaCl, but not fructose, caused modest rises in MAP (5-10 mmHg) and increased the day-to-night ratio in diastolic blood pressure. NaCl or fructose increased kidney size. Creatinine clearance was increased by salt or fat, and fractional excretion of sodium was decreased by fat. In study 1, high NaCl markedly reduced plasma renin and aldosterone and its regulated proteins in whole kidney, i.e., the thiazide-sensitive Na-Cl cotransporter and the alpha- and gamma (70-kDa band)-subunits of the epithelial sodium channel. These effects were blunted by fat. Fructose increased the abundance of the sodium phosphate cotransporter, whereas it decreased the bumetanide-sensitive Na-K-2Cl cotransporter and aquaporin-2. Overall, doubling of dietary fat appeared to impair dietary sodium adaptation, i.e., blunt the downregulation of aldosterone-mediated effects, thus allowing blood pressure to rise at an accelerated rate.
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PMID:Effects of dietary fat, NaCl, and fructose on renal sodium and water transporter abundances and systemic blood pressure. 1530 71

Low-renin hypertension responsive to amiloride-thiazide therapy in a 4-year-old Afro-Haitian girl suggested Liddle syndrome. Urine steroid profiling substantiated the diagnosis and DNA analysis of the epithelial sodium channel (ENaC) revealed a novel heterozygous beta ENaC mutation in the patient and in her hypertensive father. Liddle syndrome should be considered as a cause of hypertension in young children particularly with suppressed renin activity.
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PMID:A novel epithelial sodium channel beta-subunit mutation associated with hypertensive Liddle syndrome. 1569 Jan 92

The water and electrolyte balance is regulated by the renin-angiotensin-aldosterone system in the kidney. We previously reported that the levels of circulating aldosterone dramatically increased following a total proctocolectomy in rats. However, there is no direct evidence regarding whether renal adaptation is accelerated by the induction of aldosterone-associated molecules. To explore this question, Sprague-Dawley rats underwent total proctocolectomies and then were killed 8 weeks later. We investigated the renal expression of 11beta-hydroxysteroid dehydrogenase type 2, the alpha-, beta-, and gamma-subunits of the epithelial sodium channel, and the alpha1- and beta1-subunits of Na+,K+-ATPase mRNAs because those molecules are responsible for the aldosterone specificity for mineralocorticoid receptor, amiloride-sensitive sodium absorption, and sodium extrusion from distal tubules, respectively. A Northern blot analysis demonstrated the kidney to exhibit mRNA induction for all of these molecules, thus supporting the idea that renal adaptation following a total proctocolectomy depends, at least in part, upon the molecular induction which is principally regulated by circulating aldosterone.
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PMID:Renal expression of the essential genes associated with sodium transport following a total proctocolectomy in rats. 1591 2

Mendelian forms of hypertension have ushered in a revolution in our knowledge of blood pressure and volume regulation. If we include information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension. The latter discovery has elucidated how mutations may modify the receptor sufficiently to allow erstwhile antagonists to have an agonistic action. The epithelial sodium channel (ENaC) has been elucidated. Gain-of-function mutations in the beta and gamma subunits of ENaC cause Liddle's syndrome. Loss-of-function mutations in all three subunits of ENaC cause hypotension (pseudohypoaldosteronism type I). Thus, all three subunits can be mutated, causing either hyper or hypotension. Three loci have been described for Gordon's syndrome, pseudohypoaldosteronism type II. Two members of the WNK serine-threonine kinase family have recently been found to be responsible. Their function has been largely elucidated. Autosomal dominant hypertension with brachydactyly features normal sodium and renin-angiotensin-aldosterone responses. The gene has been mapped to chromosome 12p. The condition is interesting because it may represent a novel neural form of hypertension. Finally, at least 5 different genes have been described that when mutated can cause pheochromocytoma. Thus, the elucidation of Mendelian blood pressure-regulatory disorders has been a resounding success.
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PMID:Mendelian forms of human hypertension and mechanisms of disease. 1593 22

Hypertension in blacks is more prevalent and less often controlled than the hypertension of other ethnic groups. We sought to explore the benefit of adding inhibitors of the epithelial sodium channel (ENaC), an aldosterone-regulated site of sodium reabsorption in the distal nephron, to the antihypertensive regimen of black hypertensive patients. In a prospective, randomized, placebo-controlled, double-blind clinical trial, we used a 2-by-2 factorial design with 4 treatment groups: amiloride (a direct inhibitor of ENaC), spironolactone (an aldosterone receptor antagonist), the combination of both drugs, and placebo. The subjects (n=98) had an elevated blood pressure despite treatment that included a diuretic and a calcium channel blocker; the level of plasma renin activity was < or =0.56 ng/L per second. The primary end points were changes from baseline in systolic and diastolic blood pressure over a 9-week period of treatment. The reductions in systolic and diastolic blood pressures (mm Hg) were, respectively, 9.8+/-1.6 (SE) and 3.4+/-1.0 for amiloride (P<0.001) and 4.6+/-1.6 (P=0.006) and 1.8+/-1.0 for spironolactone (P=0.07). Treatment with either amiloride or spironolactone or the combination was well tolerated; no patient experienced hyperkalemia. In a substudy, plasma endothelin-1 levels were observed to decrease after 3 weeks of treatment with spironolactone (P<0.001), consistent with a non-ENaC-related potential benefit of spironolactone. In conclusion, treatment with either amiloride or spironolactone can provide an additional reduction in blood pressure in blacks already receiving conventional antihypertensive therapy.
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PMID:Improvement in blood pressure with inhibition of the epithelial sodium channel in blacks with hypertension. 1611 49

Prostasin is a serine peptidase hypothesized to regulate epithelial sodium channel (ENaC) activity in animals or on in vitro cultured cells. We investigated whether urinary prostasin may be a candidate marker of ENaC activation in humans. We studied 10 healthy volunteers and 8 hypertensive patients with raised aldosterone-to-renin ratio before and after spironolactone or saline/Florinef suppression test, respectively. Four healthy subjects were also studied before and after saline. Urinary prostasin was evaluated by SDS-PAGE, 2D maps, and Western blotting. Every sample of normotensive individuals was compared with the corresponding sample of urine collected after spironolactone or saline; every sample of hypertensive patients was compared with the corresponding sample of urine collected after saline or Florinef. Prostasin was detectable in all subjects regardless of gender, dietary sodium intake, and spironolactone treatment. Spironolactone (100 mg) increased urinary Na+/K+ ratio and decreased urinary prostasin in normotensives in whom the renin/aldosterone axis was activated by a low Na+ intake, but it was ineffective in individuals with high Na+ intake. Saline infusion also reduced prostasin in normotensive subjects. In contrast, prostasin paradoxically increased in urine of patients affected by primary aldosteronism after volume expansion. By 2D immunoblotting, several protein isoforms were observed, some of them being overexpressed after inhibition tests in patients with primary aldosteronism. In addition to a "basal" aliquot of prostasin, constitutively released in human urine regardless of sodium balance and aldosterone activation, there exists a second "aldosterone-responsive" aliquot modulated by Na+ intake and potentially suitable as candidate marker of ENaC activation.
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PMID:Urinary prostasin: a candidate marker of epithelial sodium channel activation in humans. 1617 30

High dietary salt intake activates the brain renin-angiotensin system in spontaneously hypertensive rats (SHR) and Dahl S rats, resulting in sympathetic hyperactivity and hypertension. Increases of sodium concentration in cerebrospinal fluid (CSF) and/or enhanced responses to CSF sodium are considered to be involved in the high dietary salt-induced activation of central nervous system pathways in those rats. Previously we have demonstrated that intracerebroventricular injection of hypertonic saline increases the neural activity of angiotensin II-sensitive neurons trans-synaptically via endogenous angiotensins in the anterior hypothalamic area (AHA) of rats. In the present study, we examined whether the AHA angiotensin II-sensitive neuron response to hypertonic saline would differ in SHR and Dahl S rats from those of their controls. Male 15- to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY), Dahl S rats and Dahl R rats and Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Intracerebroventricular injection of hypertonic saline increased the firing rate of AHA angiotensin II-sensitive neurons. The threshold sodium concentration for the central sodium-induced increase of neural firing was lower in SHR than those of WKY, Dahl S rats, Dahl R rats and Wistar rats. The increase in neural firing induced by hypertonic saline (250 mM) was greater in SHR than those of other four kinds of rats. Similarly, the threshold sodium concentration was lower in Dahl S rats than those of WKY, Dahl R rats and Wistar rats and the increase in neural firing induced by hypertonic saline (250 mM) was greater in Dahl S rats than those of WKY, Dahl R rats and Wistar rats. In SHR, intracerebroventricular injection of the amiloride-sensitive sodium channel blocker benzamil abolished the hypertonic saline (250 mM)-induced increase in neural firing, but the sodium channel blocker itself did not affect the basal firing of these neurons. These findings indicate that central sodium-induced activation of AHA angiotensin II-sensitive neurons is enhanced in SHR and Dahl S rats.
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PMID:Enhanced central hypertonic saline-induced activation of angiotensin II-sensitive neurons in the anterior hypothalamic area of spontaneously hypertensive and Dahl S rats. 1637 40

Renal sodium reabsorption is a key determinant of final urine concentration. Our aim was to determine whether differences existed between aged and young rats in their response to water restriction with regard to the regulation of abundance of any of the major distal renal sodium transporter proteins. Male Fisher 344 x Brown Norway (F344 x BN) rats of 3-, 10-, 24-, or 31 months of age (3M, 10M, 24M, or 31M) were either water restricted (WR) for 5 days or control (ad libitum water). Major renal sodium transporters and channel subunits were evaluated by immunoblotting and immunohistochemistry. Age did not significantly affect plasma arginine vasopressin or aldosterone levels, but renin activity was only 8% in 31M-WR rats relative to 3M-WR (P<0.05). Extreme aging (31M) led to decreased outer medullary abundance of the bumetanide-sensitive Na-K-2Cl cotransporter and decreased cortical abundance of the beta- and gamma-subunits (70-kDa band) of the epithelial sodium channel (ENaC) (P<0.05). Water restriction significantly (P<0.05) increased the abundance of Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC) across ages. However, these increases were significantly blunted as rats aged. Mean band densities were increased in WR rats (relative to age controls) by 54 and 106% at 3M, but only 25 and 29% at 24M and 0 and 6% at 31M for NKCC2 and NCC, respectively. Aged F344 x BN rats have reduced basal distal tubular renal sodium transporter abundances and blunted upregulation during water restriction, which may contribute to decreased urinary concentrating capacity.
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PMID:Renal ENaC subunit, Na-K-2Cl and Na-Cl cotransporter abundances in aged, water-restricted F344 x Brown Norway rats. 1640 20


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