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)

The pathophysiology of sodium and water retention in heart failure is discussed in the context of a unifying hypothesis of body fluid volume regulation. Critical to this hypothesis is the maintenance of arterial circulatory integrity, which can be disturbed by either a reduction in cardiac output or a fall in systemic vascular resistance secondary to arterial vasodilatation, as seen in high output heart failure. The filling of the arterial circulation is sensed by receptors in the left ventricle, carotid artery, aortic arch and renal afferent arteriole. Effector mechanisms involve non-osmotic vasopressin synthesis and release, the renin-angiotensin-aldosterone system and the sympathetic nervous system. In low output heart failure non-peptide selective orally active vasopressin V2-receptor antagonists correct the hyponatremia, hypoosmolality, and water retention and decrease urinary aquaporin-2 water channels, supporting the role of vasopressin in the water retention seen in heart failure. In advanced heart failure aldosterone escape does not occur because of diminished distal delivery of sodium which also contributes to the resistance to atrial natriuretic peptide seen in heart failure. In high output cardiac failure arterial underfilling associated with arterial vasodilation stimulates activation of neurohumoral systems. Tailored specific selective inhibition of these neurohumoral systems, perhaps in combination, may enable more effective treatment of cardiac failure.
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PMID:Pathogenesis of sodium and water retention in cardiac failure. 983 76

The aim of this study was to test the hypothesis that the relative insensitivity of the ovine fetal kidney to arginine vasopressin (AVP) is due to low levels of expression of the gene for aquaporin-2 (AQP2) which encodes the AVP-regulated water channel. We report the cloning of the cDNA for the ovine AQP2 which has a major transcript at 4.2 kilobases (kb) and a minor transcript at 1.5 kb, resembling the human gene transcripts. At 40-60 days' (term = 145-150 days'), mRNA levels are very low, detectable only by reverse transcription-polymerase chain reaction (RT-PCR). By Northern blot analysis AQP2 mRNA is detectable at 75 days'. The ratio of AQP2/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA increases approximately 2.4-fold between 100 and 140 days' when it is about 41% of adult values. Both glucocorticoids and the renin-angiotensin system are involved in maturation of renal function. When fetuses at 75 or 85 days of gestation were exposed to high levels of dexamethasone for 2-3 days, mRNAs for both GAPDH and AQP2 doubled, but the ratio was unchanged. Angiotensin I, infused for 3 days at 115-120 days' gestation, increased the AQP2/GAPDH mRNA ratios by twofold (major transcript) and sixfold (minor transcript), which were highly significant (P<0.001). The increasing sensitivity of the ovine fetal kidney to AVP, from 100-140 days of gestation, is largely due to increasing AQP2 gene expression over this period.
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PMID:Ovine aquaporin-2: cDNA cloning, ontogeny and control of renal gene expression. 1041 57

Heart failure is a leading cause of morbidity and mortality. In the United States, there are more than 5 million patients with heart failure and over 500,000 newly diagnosed cases each year. Numerous advances have been made in our understanding of the pathophysiologic mechanisms contributing to sodium and water retention in this condition. Important alterations in the sympathetic nervous system and the renin-angiotensin-aldosterone system have been described in heart failure, allowing the use of mechanism-specific treatments such as beta-adrenergic receptor antagonism and angiotensin-converting enzyme inhibition. As our understanding of the roles of the natriuretic peptides and the arginine vasopressin-aquaporin-2 system in the pathophysiology of heart failure evolves, treatments directed toward the alterations in these systems in heart failure can be further developed.
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PMID:Pathophysiology of sodium and water retention in heart failure. 1180 79

Mice homozygous for a loss of function mutation of the kidney-specific NaK2Cl cotransporter, BSC1/NKCC2, do not survive. Here the effects of loss of one copy of the gene are studied. NKCC2 mRNA of NKCC2 +/- kidney was 55 +/- 6% of +/+, yet no differences were found between NKCC2 +/+ and +/- mice in BP, blood gas, electrolytes, creatinine, plasma renin concentration, urine volume and osmolality, ability to concentrate and dilute urine, and response to furosemide. When mice were challenged with 180 mM NH(4)Cl, plasma ammonia and urinary ammonia excretion were increased twofold and fivefold, respectively, but there was still no difference between the two genotypes. NKCC2 +/- mice had a near-normal level of NKCC2 protein and no clear change in the distribution of NKCC2 in the thick ascending limb (TAL) cells. In vitro microperfusion of isolated TAL showed no significant difference between the two genotypes in the basal and vasopressin-stimulated capacity to reabsorb NaCl. There was no difference in the mRNA expressions of thiazide-sensitive NaCl cotransporter, epithelial Na channel (ENaC), aquaporin-2, ROMK, and NaKATPase. Halving the mRNA expression of NKCC2 does not affect BP or fluid balance because of compensatory factors that restore the protein level to near normal. One possible factor is a regulated increase in the movement of cytoplasmic protein to the luminal membrane leading to a restoration of functional transporter to an essentially wild type level.
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PMID:Posttranscriptional compensation for heterozygous disruption of the kidney-specific NaK2Cl cotransporter gene. 1185 63

Aberrant gene-environment interactions are implicated in the pathogenesis of congenital renal dysgenesis (CRD), a leading cause of renal failure in infants and children. We have recently developed an animal model of CRD that is caused by gestational salt stress (5% NaCl diet; HS) of bradykinin B2R null mice [B2R(-/-)CRD; El-Dahr SS, Harrison-Bernard LM, Dipp S, Yosipiv IV, and Meleg-Smith S. Physiol Genomics 3: 121-131, 2000.]. Developing B2R(-/-)CRD mice exhibit tubular and glomerular cysts, stromal expansion, and loss of corticomedullary differentiation. In addition, B2R(-/-)CRD mice exhibit transient hypertension from 2 to 4 mo of age. The present study was designed to determine the long-term consequences of CRD on renal morphology and salt sensitivity of blood pressure in B2R(-/-)CRD mice. One-year- and 18-mo-old B2R(-/-)CRD mice exhibited stunted renal growth, glomerular cystic abnormalities, and collecting duct ectasia. Moreover, tumors of mesenchymal cell origin emerged in the dysplastic kidneys of 90% of 1-yr-old and 100% of 18-mo-old B2R(-/-)CRD mice but not in age-matched B2R(-/-) or wild-type mice. When challenged with an HS diet, 18-mo-old B2R(-/-)CRD exhibited a significant rise in systolic and diastolic blood pressures and more pronounced natriuresis and diuresis compared with salt-loaded 18-mo-old wild-type mice. Kidney aquaporin-2 expression was decreased by 50%, whereas renin, ANG type 1 receptor, and Na+-K+-ATPase levels were not different in B2R(-/-)CRD mice compared with controls. In conclusion, this study demonstrates that B2R(-/-)CRD mice exhibit permanent phenotypic and functional abnormalities in renal growth and differentiation. This novel model of human disease links gene-environment interactions with renal development and blood pressure homeostasis.
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PMID:Renal and blood pressure phenotype in 18-mo-old bradykinin B2R(-/-)CRD mice. 1280 91

Distal nephron renin may provide a possible pathway for angiotensin (Ang) I generation from proximally delivered angiotensinogen. To examine the effects of Ang II on distal nephron renin, we compared renin protein and mRNA expression in control and Ang II-infused rats. Kidneys from sham (n=9) and Ang II-infused (80 ng/kg per minute, 13 days, n=10) Sprague-Dawley rats were processed by immunohistochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Ang II infusion increased systolic blood pressure (181+/-4 versus 115+/-5 mm Hg) and suppressed plasma and kidney cortex renin activity. Renin immunoreactivity was suppressed in juxtaglomerular apparatus (JGA) cells in Ang II-infused rats compared with sham (0.1+/-0.1 versus 1.0+/-0.1 relative ratio) but increased in distal nephron segments (6.4+/-1.4 versus 1.0+/-0.1 cortex; 2.5+/-0.3 versus 1.0+/-0.2 medulla). Tubular renin immunostaining was apically distributed in principal cells colocalizing with aquaporin-2 in connecting tubules and cortical and medullary collecting ducts. Renin protein levels were decreased in the kidney cortex of Ang II-infused rats compared with that of sham (0.4+/-0.2 versus 1.0+/-0.4) rats but higher in the kidney medulla (1.2+/-0.4 versus 1.0+/-0.1). In kidney medulla, RT-PCR and quantitative real-time PCR showed similar levels of renin transcript in both groups. In summary, the detection of renin mRNA in the renal medulla, which is devoid of JGA, indicates local synthesis rather than an uptake of JGA renin. In contrast to the inhibitory effect of Ang II on JGA renin, Ang II infusion stimulates renin protein expression in collecting ducts and maintains renin transcriptional levels in the medulla, which may contribute to the increased intrarenal Ang II levels in Ang II-dependent hypertension.
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PMID:Enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. 1522 76

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

Clinical and laboratory experiments have demonstrated that arginine vasopressin (AVP), renin-aldosterone system and catecholamines play a crucial role in water and sodium retention in edematous diseases, including congestive heart failure, nephrotic syndrome and liver cirrhosis. These hormonal secretions are all increased mediated through baroreceptor mediated afferent pathway, in which the tonic inhibition of hormonal release is attenuated by decreased effective circulatory blood volume. Increased plasma hormones augment their action in renal tubules. AVP increases abundance of aquaporin-2 protein in renal collecting duct cells, and enhances renal water reabsorption. Aldosterone enhances sodium reabsorption in distal nephron. Also, norepinephrine increases sodium reabsorption in proximal tubules, and in part augments renin-aldosterone system that increases sodium reabsorption in distal nephron.
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PMID:[Hormones and hemodynamics in edematous diseases]. 1567 18

NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored. Therefore, we asked 1) whether NKCC1 (-/-) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether the hypotension observed in these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter expression. Thus we performed balance studies, semiquantitative immunoblotting, and immunohistochemistry of kidney tissue from NKCC1 (+/+) and NKCC1 (-/-) mice which consumed either a high (2.8% NaCl)- or a low-NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in NKCC1 (-/-) than NKCC1 (+/+) mice following either high or low dietary NaCl intake. Relative to wild-type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was either the same or only slightly increased in the mutant mice. Expression of NHE3, the alpha-subunit of the Na-K-ATPase, NCC, and NKCC2 were higher in NKCC1 null than in wild-type mice, although differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to excrete free water than wild-type mice, which resulted in hypochloremia following the NaCl-deficient diet. Hypochloremia did not occur from increased aquaporin-1 (AQP1) or 2 protein expression or from redistribution of AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary osmolality following vasopressin administration, which should increase free water excretion and attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice, which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin, and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and blood pressure, thus minimizing hypotension.
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PMID:Hypotension in NKCC1 null mice: role of the kidneys. 1615 93

The renin-angiotensin system is well known to be involved in the pathophysiological changes in renal function after obstruction of the ureter. Previously, we demonstrated that bilateral ureteral obstruction (BUO) is associated with dramatic changes in the expression of both renal sodium transporters and aquaporin water channels (AQPs). We now examined the effects of the AT(1)-receptor antagonist candesartan on the dysregulation of AQPs and key renal sodium transporters in rats subjected to 24-h BUO and followed 2 days after release of BUO (BUO-2R). Consistent with previous observations, BUO-2R resulted in a significantly decreased expression of AQP1, -2, and -3 compared with control rats. Concomitantly, the rats developed polyuria and reduced urine osmolality. Moreover, expression of the type 2 Na-phosphate cotransporter (NaPi-2) and type 1 bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) was markedly reduced, consistent with postobstructive natriuresis. Candesartan treatment from the onset of obstruction attenuated the reduction in GFR (3.1 +/- 0.4 vs. 1.7 +/- 0.3 ml.min(-1).kg(-1)) and partially prevented the reduction in the expression of AQP2 (66 +/- 21 vs. 13 +/- 2%, n = 7; P < 0.05), NaPi-2 (84 +/- 6 vs. 57 +/- 10%, n = 7; P < 0.05), and NKCC2 (89 +/- 12 vs. 46% +/- 11, n = 7; P < 0.05). Consistent with this, candesartan treatment attenuated the increase in urine output (58 +/- 4 vs. 97 +/- 5 microl.min(-1).kg(-1), n = 7; P < 0.01) and the reduction in sodium reabsorption (433 +/- 62 vs. 233 +/- 45 micromol.min(-1).kg(-1), n = 7; P < 0.05) normally found in rats subjected to BUO. Moreover, candesartan treatment attenuated induction of cyclooxygenase 2 (COX-2) expression in the inner medulla, suggesting that COX-2 induction in response to obstruction is regulated by ANG II. In conclusion, candesartan prevents dysregulation of AQP2, sodium transporters, and development of polyuria seen in BUO. This strongly supports the view that candesartan protects kidney function in response to urinary tract obstruction.
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PMID:Angiotensin II mediates downregulation of aquaporin water channels and key renal sodium transporters in response to urinary tract obstruction. 1675 30


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