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)

NO, a simple molecule synthesized from L-arginine by NO synthases, has been identified to play an important role in cell communication, cell defense and cell injury. The half life of NO is very short because NO either reacts with superoxide anion (O2-), and/or binds to heme molecules or Fe-S groups present in proteins. The biological effects of NO depend on both the concentration of NO at the site of action as well as upon the specific location where NO is generated. Small quantities of NO are generated by cNOS such as that present in the vascular endothelium, while large quantities of nitric oxide are synthesized by iNOS in response to cytokines or bacterial products. Within the kidney NO generated by endothelial cNOS participates in the regulation of the glomerular microcirculation by modifying the tone of the afferent arteriole and mesangial cells (Fig. 4). In addition, NO generated by macula densa and the afferent arteriole control glomerular hemodynamics via TGF and by modulating renin release. Therefore NO is important in the physiologic regulation of glomerular capillary blood pressure, glomerular plasma flow and the glomerular ultrafiltration coefficient. Through its actions on glomerular pressures and flows, NO may also regulate the macro- and micromolecular traffic through the mesangium. Chronic NO insufficiency causes hypertension and glomerular damage and may be causally involved in the genesis of salt dependent hypertension. Increased NO production may be involved in the early pathogenic hemodynamic changes in diabetes and in the physiologic hemodynamic responses to normal pregnancy. Maintenance of the antithrombogenic properties of the endothelium is another important action of NO which inhibits platelet aggregation and adhesion. Large quantities of NO such as that synthesized by either glomerular cells or macrophages during glomerular inflammation may lead to glomerular injury. A better understanding of the physiology and pathophysiology of NO in the kidney will lead to the development of new therapeutic avenues.
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PMID:Glomerular actions of nitric oxide. 756 80

Nitric oxide derived from vascular endothelium is a potent vasodilator that plays a key role in the homeostasis of blood pressure. Because cirrhotic patients tend to have low arterial pressure, we measured in 51 patients and 10 control subjects serum nitrite and nitrate levels as an index of in vivo nitric oxide generation. We also measured plasma endotoxin, a substance frequently increased in cirrhotic patients and known to induce nitric oxide synthesis. Cirrhotic patients showed significant increases in serum nitrite/nitrate and plasma endotoxin compared with controls. Values were particularly increased in patients with decompensated cirrhosis, as manifested by ascites with or without functional kidney failure. High serum nitrite/nitrate levels were associated with high plasma renin activity, high aldosterone and antidiuretic hormone levels and low urinary excretion of sodium. In addition, serum nitrite/nitrate levels significantly correlated with endotoxemia. Oral administration of colistin to 15 cirrhotic patients reduced significantly plasma endotoxin levels (p < 0.01) and serum nitrite/nitrate levels (p < 0.05). Because endotoxin enhances the expression of inducible nitric oxide synthase, our results suggest that circulating endotoxin in cirrhosis is responsible for excessive synthesis and release of nitric oxide by the vasculature. These findings might explain the hemodynamic dysfunction seen in cirrhotic patients.
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PMID:Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. 822 20

Experiments were performed to examine the effect of changes in dietary salt intake on the neuronal form of the constitutive nitric oxide synthase (ncNOS, type I NOS), renin, and angiotensinogen mRNA expression in the kidney. Three groups of Sprague-Dawley rats were studied as follows: rats maintained on a 3% Na diet plus 0.45% NaCl in the drinking fluid for 7 days (high salt), rats given a single injection of furosemide (2 mg/kg i.p.) and a 0.03% Na diet for 7 days (low salt), and rats on a diet containing 0.2% Na (control). mRNA expression was assessed with reverse transcription-polymerase chain reaction (RT-PCR) methods using cDNA prepared from samples of renal cortex and microdissected tubular segments. ncNOS PCR products were quantified by comparison with a dilution series of a mutant deletion template. Compared with their respective control, ncNOS mRNA levels in renal cortical tissue were elevated in rats on a low-salt diet and reduced in rats on a high-salt diet. Similar changes were seen in the expression of renin and angiotensinogen mRNA. Dietary salt intake did not alter the mRNA levels for ncNOS from the inner medulla or for endothelial constitutive NOS (ecNOS, type III NOS) and inducible NOS (iNOS, type II NOS) in the renal cortex. ncNOS mRNA was found in glomeruli dissected with the macula densa-containing segment (MDCS), but only at marginal levels in glomeruli without MDCS. Furthermore, a low-salt diet stimulated ncNOS mRNA in glomeruli with MDCS by 6.2-fold compared with a high-salt diet. There was no effect of salt diet on ncNOS mRNA in glomeruli without MDCS or in inner medullary collecting ducts. These results suggest that ncNOS expression in macula densa cells is inversely regulated by salt intake, thus following the known response of the renin-angiotensin system to changes in salt balance.
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PMID:Coordinate regulation of renal expression of nitric oxide synthase, renin, and angiotensinogen mRNA by dietary salt. 876 22

Nitric oxide produced in endothelial cells affects vascular tone. To investigate the role of endothelial nitric oxide synthase (eNOS) in blood pressure regulation, we have generated mice heterozygous (+/-) or homozygous (-/-) for disruption of the eNOS gene. Immunohistochemical staining with anti-eNOS antibodies showed reduced amounts of eNOS protein in +/- mice and absence of eNOS protein in -/- mutant mice. Male or female mice of all three eNOS genotypes were indistinguishable in general appearance and histology, except that -/- mice had lower body weights than +/+ or +/- mice. Blood pressures tended to be increased (by approximately 4 mmHg) in +/- mice compared with +/+, while -/- mice had a significant increase in pressure compared with +/+ mice (approximately 18 mmHg) or +/- mice (approximately 14 mmHg). Plasma renin concentration in the -/- mice was nearly twice that of +/+ mice, although kidney renin mRNA was modestly decreased in the -/- mice. Heart rates in the -/- mice were significantly lower than in +/- or +/+ mice. Appropriate genetic controls show that these phenotypes in F2 mice are due to the eNOS mutation and are not due to sequences that might differ between the two parental strains (129 and C57BL/6J) and are linked either to the eNOS locus or to an unlinked chromosomal region containing the renin locus. Thus eNOS is essential for maintenance of normal blood pressures and heart rates. Comparisons between the current eNOS mutant mice and previously generated inducible nitric oxide synthase mutants showed that homozygous mutants for the latter differ in having unaltered blood pressures and heart rates; both are susceptible to lipopolysaccharide-induced death.
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PMID:Elevated blood pressures in mice lacking endothelial nitric oxide synthase. 891 64

We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8 versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1 mg/g; P<0. 001). PDTC reduced 24-hour albuminuria by >95% (2.5+/-0.8 versus 57. 1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.
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PMID:NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. 1064 97

Leukocyte infiltration and adhesion molecule activation play a central role in the pathogenesis of angiotensin II (Ang II)-induced end-organ damage in double transgenic rats (dTGR) harboring human renin and angiotensinogen genes. We tested the hypothesis that the immunosuppressive agent cyclosporine (CsA) protects against the Ang II-induced myocardial and renal damage in dTGR. Furthermore, we investigated the influence of CsA on interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expression and the DNA binding activity of transcription factor necrosis factor-kappaB (NF-kappaB). The 4-week-old rats were divided into 4 groups: (1) control dTGR (n=20), (2) dTGR plus CsA (5 mg/kg SC for 3 weeks, n=15), (3) normotensive Sprague-Dawley (SD) rats (n=10), and (4) SD rats plus CsA (n=8). In dTGR, CsA completely prevented cardiovascular death (0 of 15 versus 9 of 20), decreased 24-hour albuminuria by 90% and systolic blood pressure by 35 mm Hg, and protected against the development of cardiac hypertrophy. Whole blood CsA concentrations 24 hours after the last drug treatment were 850+/-15 ng/mL. Semiquantitative ED-1 and Ki-67 (a nuclear cell proliferation-associated antigen) scoring showed that CsA prevented perivascular monocyte/macrophage infiltration and prevented cell proliferation in the kidneys and hearts of dTGR, respectively. The beneficial effects of CsA were, at least in part, mediated by the suppression of IL-6 and iNOS expression. Electrophoretic mobility shift assay revealed that CsA regulated inflammatory response in part through the NF-kappaB transcriptional pathway. In contrast to dTGR, CsA increased blood pressure in normotensive SD rats by 10 mm Hg and had no effect on cardiac mass or 24-hour urinary albumin excretion. Perivascular monocyte/macrophage infiltration, IL-6, and iNOS expression or cell proliferation were not affected by CsA in SD rats. Our findings indicate that CsA protects against Ang II-induced end-organ damage and underscore the central role of vascular inflammatory response in the pathogenesis of myocardial and renal damage in dTGR. The beneficial effects of CsA in the kidney and heart are mediated, at least in part, by suppression of IL-6 and iNOS expression via NF-kappaB transcriptional pathway.
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PMID:Cyclosporin A protects against angiotensin II-induced end-organ damage in double transgenic rats harboring human renin and angiotensinogen genes. 1064 25

The goal of this study was to determine the role of inducible nitric oxide synthase (iNOS) in the arterial pressure, renal hemodynamic, renal excretory, and hormonal changes that occur in Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats during changes in Na intake. Thirty-two R and S rats, equipped with indwelling arterial and venous catheters, were subjected to low (0.87 mmol/day) or high (20.6 mmol/day) Na intake, and selective iNOS inhibition was achieved with intravenous aminoguanidine (AG, 12.3 mg. kg(-1). h(-1)). After 5 days of AG, mean arterial pressure increased to 121 +/- 3% control in the R-high Na AG rats compared with 98 +/- 1% control (P < 0.05) in the R-high Na alone rats, and S-high Na rats increased their arterial pressure to 123 +/- 3% control compared with 110 +/- 2% control (P < 0.05) in S-high Na alone rats. AG caused no significant changes in renal hemodynamics, urinary Na or H(2)O excretion, plasma renin activity, or cerebellar Ca-dependent NOS activity. The data suggest that nitric oxide produced by iNOS normally helps to prevent salt-sensitive hypertension in the Dahl R rat and decreases salt sensitivity in the Dahl S rat.
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PMID:Mechanisms of salt-sensitive hypertension: role of inducible nitric oxide synthase. 1108 98

The benefit effects of nitric oxide (NO) donors in acute heart failure have led to the development of vasodilators as treatment of chronic heart failure. However, the mechanisms involved in the effects of NO are complex and still discussed. In chronic heart failure, the eNOS downregulation in vascular endothelium explains the alteration of endothelial function. In addition, in the myocardium, cytokines induce the expression of inducible nitric oxide synthase (iNOS) which increase NO production by myocytes and surrounding cells. This excess of NO production, associated with anion superoxide synthesis, limits the inotropic properties of catecholamines and exert proapoptotic effects. The role of NO donors in heart failure treatment is still controversial but by reducing preload they improve patient's symptoms. Beside blockade of the renin-angiotensin system, the angiotensin converting enzyme inhibitors act via the inhibition of bradykinin degradation which increase NO levels. Finally, vascular endothelial NO expression is improved by exercise training and participates in the improvement of exercise capacity in patients with chronic heart failure involved in cardiac readaptation program.
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PMID:[Role of nitric oxide in heart failure]. 1132 16

Binding of angiotensin II on the angiotensin II type-1 receptor induces cell growth, while triggering via the angiotensin II type-2 (AT(2)) receptor causes an opposing effect of growth inhibition and apoptosis. AT(2) receptor stimulation has also been shown to enhance inducible nitric oxide synthase (iNOS) expression, an enzyme associated with cancer. To study the involvement of the angiotensin II receptors and iNOS in the carcinogenesis of human breast, we visualised both factors in tissues from patients with hyperplasia, ductal carcinoma in situ (DCIS) and invasive carcinoma using immunocytochemistry and in situ hybridisation. In normal ducts, levels for AT(2) protein and mRNA are low, but these are markedly increased in all pathological tissues. While in normal tissue both negative and positive ducts are found, the staining patterns in hyperplasia, DCIS and invasive carcinoma have a homogeneous positive appearance. Similarly, iNOS enzyme expression was very low in the ductal epithelium of normal tissues, but highly increased in all pathologies, with the highest expression found in hyperplastic ducts. Three human cell lines were assayed for the presence of AT(2) receptor. Normal HMec 1001-3 cells were weakly positive, but only one of the adenocarcinoma cell lines, designated SK-BR-3, was shown to express both AT(2) protein and its mRNA. We show that AT(2) receptor and iNOS overexpression are associated with breast disease, further confirming the involvement of the components of the renin-angiotensin system in the aetiology of breast cancer.
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PMID:Increased angiotensin II type-2 receptor density in hyperplasia, DCIS and invasive carcinoma of the breast is paralleled with increased iNOS expression. 1181 93

Despite extensive research, the exact mechanisms of cyclosporine A (CsA)-induced hypertension and nephrotoxicity remain obscure. Several lines of evidence suggest an involvement of the renin-angiotensin system (RAS) in CsA toxicity, but the issue is still controversial in more ways than one. Some interesting data of the interaction of CsA and RAS have been presented by us and others during the last years. In rats, activation of RAS by CsA is a consistent finding while the results from clinical studies show controversial results. The mechanisms of activation of RAS may be multifactorial. CsA increases renin release directly from juxtaglomerular cells. However, RAS activation may at least partly account for glomerular ischemia by vasoconstriction. A totally different view about the interaction of CsA and RAS has recently been presented. CsA antagonised the harmful effects of RAS over-expression on renal damage in double transgenic rats harbouring human renin and angiotensinogen genes. The protection was due to anti-inflammatory properties of CsA by inhibition of interleukin-6 and inducible nitric oxide synthase (iNOS) expression. Other studies have confirmed the inhibitory effect of CsA on iNOS. Calcium antagonists have been proposed to be the antihypertensive drugs of choice in treatment of CsA-induced hypertension because of their favourable haemodynamic effects on the kidneys. However, because angiotensin II plays a major role in the development of CsA-induced structural renal damage, pharmacological inhibition of RAS in CsA-treatment may have some beneficial effects beyond blood pressure control.
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PMID:Interaction of cyclosporine A and the renin-angiotensin system; new perspectives. 1187 76


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