bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma renin in mice with one or two renin genes
Authors: Hansen P. B. , Yang T. , Huang Y. , Mizel D. , Briggs J. , Schnermann J. 
Published: July 2004

AbstractAim:  In the present study we have investigated whether the presence of a second renin gene exerts an overriding influence on plasma renin such that mice with two renin genes have consistently higher renin levels than mice with only one renin gene.Methods:  Plasma renin was determined as the rate of angiotensin I generation using a radioimmunoassay (RIA) kit with (plasma renin concentration, PRC) or without (plasma renin activity, PRA) the addition of purified rat angiotensinogen as substrate.Results:  In male 129SvJ, DBA/2 and Swiss Webster mice, strains possessing both Ren‐1 and Ren‐2, PRC (ng Ang I mL−1 h−1) averaged 178 ± 36, 563 ± 57 and 550 ± 43 while PRA was 2.9 ± 0.5, 3.6 ± 0.8 and 7.8 ± 1.2. In male C57BL/6, C3H and BALB/c mice that express only Ren‐1, PRC averaged 426 ± 133, 917 ± 105 and 315 ± 72, and PRA was 3.4 ± 1.0, 6.9 ± 1.7 and 4.5 ± 1.2. In the two renin gene A1AR−/− mice compared with the one renin gene A1AR+/+, PRC averaged 538 ± 321 and 415 ± 159 while PRA averaged 3.2 ± 1.1 and 4.4 ± 1.4 ng Ang I mL−1 h−1. Aldosterone levels showed no significant differences between one renin (C57BL/6, C3H and BALB/c) and two renin (129SvJ, DBA/2 and Swiss Webster) gene mice. Furthermore, by quantitative real‐time polymerase chain reaction (RT‐PCR) we found no correlation between the number of renin genes and whole kidney renin mRNA levels from one and two renin gene mice.Conclusion:  Our data show that baseline plasma renin is not systematically higher in mice with two renin genes than in one renin gene mice. Thus, the presence of a second renin gene does not seem to be a major determinant of differences in PRC between different mouse strains.
Mechanisms for macula densa cell release of renin
Authors: Persson A. E. G. , Ollerstam A. , Liu R. , Brown R. 
Published: July 2004

AbstractThe juxtaglomerular apparatus in the kidney is important in controlling extracellular fluid volume and renin release. The fluid load to the distal tubule is first sensed at the macula densa site via the entry of NaCl, through a Na, K, 2Cl co‐transport mechanism. The next step is unclear, but there is recent evidence of an increased macula densa cell calcium concentration with a reduction in fluid load to the macula densa. An increase in macula densa cell calcium could activate phospholipase A2 to release arachidonic acid, the rate‐limiting step in the formation of prostaglandins. Recent evidence suggests that the prostaglandin formed is PGE2, a potent stimulator for renin release. Recent evidence has also shown that adenosine has an important function in the juxtaglomerular apparatus. It stimulates calcium release in afferent arteriolar smooth muscle cells, leading to contraction of the afferent arteriole as part of the tubuloglomerular feedback mechanism, and inhibits renin release. Thus, renin release from the afferent arteriole is mediated partly through formation of PGE2, and partly through the reduction of adenosine formation that inhibits renin production.
Mechanisms underlying the antihypertensive functions of the renal medulla
Authors: Bergström G. , Evans R. G. 
Published: July 2004

AbstractThere is good evidence that the renal medulla plays a pivotal role in long‐term regulation of blood pressure. ‘Renal medullary’ blood pressure regulating systems have been postulated to involve both exocrine (pressure natriuresis/diuresis) and endocrine [renal medullary depressor hormone (RMDH)] functions. However, recent studies indicate that pressure diuresis/natriuresis dominates the antihypertensive renal response to increased renal perfusion pressure, suggesting little physiological role for a putative RMDH in compensatory responses to acutely increased blood pressure. The medullary circulation appears to play a key role in mediating pressure diuresis, although the precise mechanisms involved remain controversial. Counter‐regulatory vasodilator mechanisms (e.g. nitric oxide), at least partly mediated through cross‐talk between the vasculature and the tubular epithelium, protect the medullary circulation from the vasoconstrictor effects of hormonal factors such as angiotensin II. These mechanisms also appear to contribute to compensatory responses to increased salt intake in salt‐resistant individuals. Failure of these mechanisms predisposes the organism towards the development of hypertension, appears to underlie the development of some forms of experimental hypertension, and may even contribute to the pathogenesis of essential hypertension.
Volume natriuresis vs. pressure natriuresis
Authors: Bie P. , Wamberg S. , Kjolby M. 
Published: July 2004

AbstractBody fluid regulation depends on regulation of renal excretion. This includes a fast vasopressin‐mediated water‐retaining mechanism, and slower, complex sodium‐retaining systems dominated by the renin–angiotensin aldosterone cascade. The sensory mechanisms of sodium control are not identified; effectors may include renal arterial pressure, renal reflexes, extrarenal hormones and other regulatory factors. Since the pioneering work of Guyton more than three decades ago, pressure natriuresis has been in focus. Dissociations between sodium excretion and blood pressure are explained as conditions where regulatory performance exceeds the precision of the measurements. It is inherent to the concept, however, that sudden transition from low to high sodium intake elicits an arterial pressure increase, which is reversed by the pressure natriuresis mechanism. However, such transitions elicit parallel changes in extracellular fluid volume thereby activating volume receptors.Recently we studied the orchestration of sodium homeostasis by chronic and acute sodium loading in normal humans and trained dogs. Small increases in arterial blood pressure are easily generated by acute sodium loading, and dogs appear more sensitive than humans. However, with suitable loading procedures it is possible – also acutely – to augment renal sodium excretion by at least one order of magnitude without any change in arterial pressure whatsoever. Although pressure natriuresis is a powerful mechanism capable of overriding any other controller, it seems possible that it is not operative under normal conditions. Consequently, it is suggested that physiological control of sodium excretion is neurohumoral based on extracellular volume with neural control of renin system activity as an essential component.
Pharmacotyping of hypokalaemic salt‐losing tubular disorders
Authors: Reinalter S. C. , Jeck N. , Peters M. , Seyberth H. W. 
Published: July 2004

AbstractLong standing confusion exists in the terminology of hypokalaemic salt‐losing tubulopathies (SLTs). SLTs are autosomal recessively transmitted and characterized by normotensive secondary hyperreninism/hyperaldosteronism with hypokalaemic metabolic alkalosis. Historically, four phenotypical variants have been described: (1) the (classic) Bartter syndrome (cBS), (2) the hypomagnesaemic hypocalciuric Gitelman syndrome (GS), (3) the hypercalciuric hyperprostaglandin‐E‐syndrome (HPS) or antenatal Bartter syndrome (aBS) and (4) the hyperprostaglandin‐E‐syndrome with sensorineural deafness (HPS + SND). The latter two syndromes are the most severe variants with antenatal manifestation with polyhydramnios and life‐threatening course of salt‐ and water‐loss. Defects in five renal membrane proteins involved in electrolyte reabsorption have been identified: In HPS‐patients mutations in (1) either the furosemide‐sensitive sodium–potassium–chloride cotransporter NKCC2, or (2) in the potassium channel ROMK have been identified, and (3) HPS + SND is caused by mutations in the β‐subunit of the chloride channels ClC‐Kb and –Ka (named barttin), all mimicking the major pharmacological effects of furosemide with minor potassium‐wasting in ROMK‐patients as seen in patients treated with simultaneous furosemide and amiloride, and minor calcium‐wasting in Barttin‐patients resembling the combination of furosemide and thiazides. (4) cBS is caused by mutations in the chloride channel ClC‐Kb with similar clinical characteristics as seen under combination of thiazides and furosemide, (5) GS is caused by mutations in the thiazide‐sensitive sodium‐chloride cotransporter NCCT resembling the effect of long‐term thiazide administration.Conclusion:  The combination of pharmacology and genetics suggests a new terminology for the above described SLTs: Furosemide‐like‐SLT for HPS caused by NKCC2‐mutations, furosemide/amiloride‐like‐SLT for HPS caused by ROMK‐mutations, furosemide/thiazide‐like‐SLT for HPS + SND, thiazide/furosemide‐like‐SLT for cBS, and thiazide‐like‐SLT for GS.
The role of cyclooxygenases and prostanoid receptorsin furosemide‐like salt losing tubulopathy:the hyperprostaglandin E syndrome
Authors: Nüsing R. M. , Seyberth H. W. 
Published: July 2004

AbstractHyperprostaglandin E syndrome/antenatal Bartter syndrome is characterized by NaCl wasting and volume depletion, juxtaglomerula hypertrophy, hyper‐reninism and secondary hyperaldosteronism. Primary causes are mutations in the gene for Na‐K‐2Cl‐cotransporter, NKCC2, or for potassium channel, ROMK, responsible for medullary NaCl malabsorption. Most intriguing aspect of the syndrome is the association with a massively increased renal prostaglandin production which contributes substantially to the clinical picture of the patients. Therefore the term hyperprostaglandin E syndrome has been introduced. It is unclear how prostaglandins aggravate the NaCl transport deficiency. Aspects to prostaglandin synthesis and receptor‐mediated function within the kidney in patients suffering from hyperprostaglandin E syndrome/antenatal Bartter syndrome will be discussed.
The renin–angiotensin system in kidney development
Authors: Chen Y. , Lasaitiene D. , Friberg P. 
Published: July 2004

AbstractAll components of the renin–angiotensin system (RAS) are highly expressed in the developing kidney in a pattern suggesting a role for angiotensin II in renal development. In support of this notion, pharmacological interruption of angiotensin II type‐1 (AT1) receptor signalling in animals with an ongoing nephrogenesis produces specific renal abnormalities characterized by papillary atrophy, abnormal wall thickening of intrarenal arterioles, tubular atrophy associated with expansion of the interstitium, and a marked impairment in urinary concentrating ability. Similar changes in renal morphology and function develop also in mice with targeted inactivation of genes encoding renin, angiotensinogen, angiotensin‐converting enzyme, or both AT1 receptor isoforms simultaneously. Taken together, these results clearly indicate that an intact signalling through AT1 receptors is a prerequisite for normal renal development. The present report mainly reviews the renal abnormalities induced by blocking the RAS pharmacologically in experimental animal models. In addition, pathogenetic mechanisms are discussed.
Cyclooxygenase‐2 and the renal renin–angiotensin system
Authors: Harris R. C. , Zhang M.‐Z. , Cheng H.‐F. 
Published: July 2004

AbstractIn the kidney, cyclooxygenase‐2 (COX‐2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na+/K+/2Cl− cotransport, and administration of non‐specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX‐2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX‐2 expression. In AT1 receptor knockout mice, COX‐2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX‐2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX‐2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX‐2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX‐2 inhibitor but not a COX‐1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low‐salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX‐2‐selective inhibitors. In mice with genetic deletion of COX‐2, ACE inhibitors or low‐salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX‐1 null mice there were no significant differences in either the basal or ACE inhibitor‐stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX‐2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX‐2 derived prostaglandins and the renin–angiotensin system may underlie physiological and pathophysiological regulation of renal function.
The renin–angiotensin system in kidney development: role of COX‐2 and adrenal steroids
Authors: Jensen B. L. , Stubbe J. , Madsen K. , Nielsen F. T. , Skøtt O. 
Published: July 2004

AbstractRecent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin–angiotensin–aldosterone system (RAAS) and cyclooxygenase type‐2 (COX‐2) are necessary for late stages of kidney development. The present review summarizes data on the developmental changes of RAAS and COX‐2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay significantly elevated in the suckling period while aldosterone stabilizes at an adult level. COX‐2 is stimulated in thick ascending limb of Henle's loop in the suckling period at a time when urine concentrating ability is not developed. Data suggest that this induction is mediated by combined low plasma glucocorticoid concentration and by a low NaCl intake. Studies with selective inhibitors of COX‐2 and COX‐2 null mice show that COX‐2 activity stimulates renin secretion from JG‐cells during postnatal kidney development and that lack of COX‐2 activity leads to pathological change in cortical architecture and eventually to renal failure. In the postnatal period, ANG II initiates and maintains pelvic and ureteric contractions necessary for urine flow. Lack of ANG II in the neonatal period is thought to cause injury by a chronic increase of renal pelvic pressure. Aldosterone is crucial for survival and growth in the neonatal period through its effects on sodium reabsorption and the intrarenal sensitivity to aldosterone is increased in the postnatal period. Final maturation of the kidney occurs through an intimate interplay between a low dietary sodium intake and a non‐responsive HPA‐axis which stimulates cortical COX‐2 activity. COX‐2 supports increased activity of the RAAS and may contribute to a low concentrating ability.
Are there clinical phenotypes of homozygous sickle cell disease?
Authors: Alexander Neal , Higgs Douglas , Dover George , Serjeant Graham R. 
Published: July 2004

SummaryThe distribution of clinical features was examined in subjects with homozygous sickle cell (SS) disease in the Jamaican Cohort Study to determine whether there is evidence of distinct clustering of symptoms or clinical phenotypes. A twofold model yielded groups that could be interpreted as painful crisis or leg ulcer phenotypes and 78% of patients were classified with 95% confidence into one of these. The painful crisis phenotype also manifested higher frequencies of dactylitis, meningitis/septicaemia, acute chest syndrome and stroke. Attempts to define a three‐group model were less convincing although 43% of patients could be allocated with 95% confidence. The three‐group model essentially divided subjects with the leg ulcer phenotype into subgroups with higher and lower frequencies of painful crisis, dactylitis, meningitis/septicaemia and acute chest syndrome. In the three‐group model, the painful crisis phenotype had lower total haemoglobin, fetal haemoglobin, mean cell volume and higher reticulocytes but there was no apparent influence of alpha thalassaemia or beta globin haplotype. Both environmental and genetic factors are likely to contribute to most manifestations of SS disease and the evidence for different clinical phenotypes suggests that a search for associated genetic polymorphisms may provide insights into the mechanisms of clinical variability in SS disease.
Activated protein C levels in Behçet's disease and risk of venous thrombosis
Authors: Navarro Silvia , Ricart José María , Medina Pilar , Vayá Amparo , Villa Piedad , Todolí José , Estellés Amparo , Micó María Luisa , Aznar Justo , España Francisco 
Published: July 2004

SummaryBehçet's disease is a multi‐systemic inflammatory disorder of unknown cause. Most abnormalities have been associated with endothelial injury caused by vasculitis. Thrombosis occurs in about 25% of patients, although the mechanism is unknown. The objective of this study was to evaluate the protein C activation system in Behçet's disease and its correlation with venous thromboembolism (VTE). Thirty‐nine patients (12 with VTE) and 78 age‐ and sex‐matched controls were included in the study, and levels of protein C, protein S, activated protein C (APC), protein C inhibitor (PCI), soluble thrombomodulin (TM), antithrombin (AT), α1‐antitrypsin, fibrinogen, factor VIII, von Willebrand factor (VWF) and C‐reactive protein (CRP) were measured. APC and TM levels were significantly lower in patients than in controls, whereas protein S, AT, α1‐antitrypsin, fibrinogen, factor VIII, VWF and CRP levels were significantly higher in patients than in controls. APC, PCI and TM levels were lower in patients with VTE (0·65 ± 0·19 ng/ml, 86% ± 22% and 15·5 ± 7·1 ng/ml respectively) than in those without VTE (0·78 ± 0·17 ng/ml, 100% ± 15% and 22·1 ± 15·3 ng/ml) (P < 0·05). In patients, APC levels below 0·75 ng/ml (10th percentile of the control group) increased the risk of VTE about fivefold (odds ratio = 5·1; 95% confidence interval = 1·1–23·4). These results show that reduced APC levels are associated with the high incidence of VTE in Behçet's disease.
Novel 2′‐substituted, 3′‐deoxy‐phosphatidyl‐myo‐inositol analogues reduce drug resistance in human leukaemia cell lines with an activated phosphoinositide 3‐kinase/Akt pathway
Authors: Tabellini Giovanna , Tazzari Pier Luigi , Bortul Roberta , Billi Anna Maria , Conte Roberto , Manzoli Lucia , Cocco Lucio , Martelli Alberto M. 
Published: July 2004

SummaryActivation of the phosphoinositide 3‐kinase (PI3‐K)/Akt signalling pathway has been linked with resistance to chemotherapeutic drugs, and its down‐regulation, by means of pharmacological inhibitors of PI3‐K, considerably lowers resistance to various types of therapy in cell lines derived from solid tumours. Recently, a new class of Akt inhibitors, referred to as phosphatidylinositol ether lipids (PIAs), have been synthesized. We tested whether two new PIAs could lower the sensitivity threshold to chemotherapeutic drugs of human leukaemia cell lines with an activated PI3‐K/Akt network. We used HL60AR (for apoptosis resistant), K562 and U937 cells. The two pharmacological inhibitors, used at 5 μmol/l, down‐regulated Akt kinase activity and phosphorylation. Neither of the two chemicals affected the activity of other signalling proteins in the Akt pathway, such as phosphoinositide‐dependent protein kinase‐1 or PTEN. When employed at 5 μmol/l, the Akt inhibitors markedly reduced the resistance of the leukaemic cell lines to etoposide or cytarabine. Remarkably, a 5 μmol/l concentration of the inhibitors did not negatively affect the survival rate of human cord blood CD34+ cells. Overall, our results indicate that new selective Akt pharmacological inhibitors might be used in the future for overcoming Akt‐mediated resistance to therapeutic treatments of acute leukaemia cells.
A single, multiplex analysis for all relevant activating NRAS gene mutations using heteroduplex generators
Authors: Belli Carolina , Bowen Derrick J. , Brasi Carlos De , Larripa Irene 
Published: July 2004

SummaryWe describe a multiplex polymerase chain reaction (PCR)‐based test that detected all relevant NRAS activating mutations using a single PCR followed directly by electrophoresis. The test uses a Universal Heteroduplex Generator (UHG) to detect exon‐2 (codon 61) NRAS mutations in multiplex with an UHG for exon‐1 (codons 12 and 13). The method differentiated all 19 relevant mutations in these exons and showed a mutation independent sensitivity of approximately 6%. The sensitive, specific detection of all NRAS activating mutations using this single rapid test represents a minimum workload and could be applied readily for large‐scale screening and for routine analysis.
Rapamycin‐mediated induction of γ‐globin mRNA accumulation in human erythroid cells
Authors: Mischiati Carlo , Sereni Alessia , Lampronti Ilaria , Bianchi Nicoletta , Borgatti Monica , Prus Eugenia , Fibach Eitan , Gambari Roberto 
Published: July 2004

SummaryThe present study aimed to determine whether rapamycin could increase the expression of γ‐globin genes in human erythroid cells. Rapamycin is a macrocyclic lactone that possesses immunosuppressive, antifungal and anti‐tumour properties. This molecule is approved as an immunosuppressive agent for preventing rejection in patients receiving organ transplantation. To verify the activity of rapamycin, we employed two experimental cell systems, the human leukaemia K562 cell line and the two‐phase liquid culture of human erythroid progenitors isolated from normal donors and patients with β‐thalassaemia. The results suggested that rapamycin, when compared with cytosine arabinoside, mithramycin and cisplatin, is a powerful inducer of erythroid differentiation and γ‐globin mRNA accumulation in human leukaemia K562 cells. In addition, when normal human erythroid precursors were cultured in the presence of rapamycin, γ‐globin mRNA accumulation and fetal haemoglobin (HbF) production increased to levels that were higher than those obtained using hydroxyurea. These effects were not associated with inhibition of cell growth. Furthermore, rapamycin was found to increase HbF content in erythroid precursor cells from four β‐thalassaemia patients. These results could have practical relevance, because pharmacologically mediated regulation of the expression of human γ‐globin genes, leading to increased HbF, is considered a potential therapeutic approach in haematological disorders, including β‐thalassaemia and sickle cell anaemia.