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)

Pseudohypoaldosteronism is a hereditary salt-wasting syndrome usually seen in infancy with weight loss, dehydration, and failure to thrive. The pathophysiologic origin of pseudohypoaldosteronism is unknown. The defect could be related to the unresponsiveness of target organs to mineralocorticoids resulting in hyponatremia, hyperkalemia, and markedly elevated plasma aldosterone and renin levels. Red blood cell Na+, K(+)-ATPase activity was measured in a pair of twins with pseudohypoaldosteronism, in an unrelated child with hypoaldosteronism, and in an age-matched group of 50 healthy infants and young children. The enzyme was assayed by a method that couples ATP hydrolysis with NADH oxidation. Plasma renin and aldosterone levels were measured by RIA. Red blood cell Na+, K(+)-ATPase activity in the twins with pseudohypoaldosteronism was very low at the time of diagnosis (3 wk). In both twins a time-related gradual increase in enzyme activity was observed during the 1st mo of life, reaching control values between 6 and 8 mo of age. This increase was associated with both a reduction in salt requirement and clinical improvement. Plasma renin activity and aldosterone levels were very high at the time of diagnosis. Plasma renin activity reverted gradually to normal values, whereas aldosterone levels remained high throughout the follow-up period. The child with hypoaldosteronism had normal Na+, K(+)-ATPase activity at diagnosis and during follow-up.
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PMID:Reduced Na+, K(+)-ATPase activity in patients with pseudohypoaldosteronism. 819 May 30

The endogenous activity of the local renin-angiotensin system (RAS) and the anti-ischaemic properties of captopril were investigated in electrically driven rabbit Langendorff hearts (constant pressure: 70 cmH2O, Tyrode solution, Ca2+ 1.8 mmol.l-1). Cumulative concentration-response curves showed no significant difference (P > 0.05) between the reduction of the global coronary flow (CF) by exogenous angiotensin-I or angiotensin-II (EC50 = 10(-10) mol.l-1). It is concluded that the local RAS in isolated rabbit hearts is highly sensitive, whereas its endogenous activity is very low due to very low endogenous angiotensin-I content. Myocardial ischaemia (MI) was induced by the occlusion of a left coronary artery branch and MI was quantified from NADH surface fluorescence photography. MI was significantly enlarged (+35%) (P < 0.05) by exogenous angiotensin-I (6 x 10(-9) mol.l-1). The reduction in CF and the increment in MI by angiotensin-I could be completely prevented by adding captopril at a low concentration (10(-6) mol.l-1) to the perfusion buffer. In the absence of exogenous angiotensin-I, captopril alone (10(-6) mol.l-1) neither significantly enhanced CF (P > 0.05), nor diminished MI (P > 0.05), supporting the finding of very low endogenous activity of the local RAS in this model. We, moreover, conclude that at a low concentration (10(-6) mol.l-1) captopril does not possess direct cardioprotective properties independent of its ACE inhibiting action.
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PMID:Deleterious effect of exogenous angiotensin-I on the extent of regional ischaemia and its inhibition by captopril. 843 77

Angiotensin II is a multifunctional hormone that affects both contraction and growth of vascular smooth muscle cells through a complex series of intracellular signaling events initiated by the interaction of angiotensin II with the AT1 receptor. The cellular response to angiotensin II is multiphasic, involving stimulation within seconds of phospholipase C and Ca2+ mobilization; activation within minutes of phospholipase D, A2, protein kinase C, and MAP kinase; and stimulation after a period of hours of gene transcription and NADH/NADPH oxidase activity. Angiotensin II also activates numerous intracellular tyrosine kinases. In this respect, it shares some aspects of signaling with growth factor and cytokine receptors, including activation of phospholipase C-gamma, src, and ras; association of shc with grb2; and stimulation of the Jak/STAT pathway. The cellular events responsible for this unique series of events may involve receptor movement and the creation of a signaling domain. Elucidation of these pathways is important to our understanding of AT1 receptor function as a final effector of the renin-angiotensin system.
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PMID:Angiotensin II signaling in vascular smooth muscle. New concepts. 903 29

Monocyte infiltration into the vessel wall, a key initial step in the process of atherosclerosis, is mediated in part by monocyte chemoattractant protein-1 (MCP-1). Hypertension, particularly in the presence of an activated renin-angiotensin system, is a major risk factor for the development of atherosclerosis. To investigate a potential molecular basis for a link between hypertension and atherosclerosis, we studied the effects of angiotensin II (Ang II) on MCP-1 gene expression in rat aortic smooth muscle cells. Rat smooth muscle cells treated with Ang II exhibited a dose-dependent increase in MCP-1 mRNA accumulation that was prevented by the AT1 receptor antagonist losartan. Ang II also activated MCP-1 gene transcription. Inhibition of NADH/NADPH oxidase, which generates superoxide and H2O2, with diphenylene iodonium or apocynin decreased Ang II-induced MCP-1 mRNA accumulation. Induction of MCP-1 gene expression by Ang II was inhibited by catalase, suggesting a second messenger role for H2O2. The tyrosine kinase inhibitor genistein and the mitogen-activated protein kinase kinase inhibitor PD098059 inhibited Ang II-induced MCP-1 gene expression, consistent with a mitogen-activated protein kinase-dependent signaling mechanism. Ang II may thus promote atherogenesis by direct activation of MCP-1 gene expression in vascular smooth muscle cells.
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PMID:Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. 979 45

Angiotensin II and hypertension increase vascular oxidant stress. We examined how these might affect expression of the extracellular superoxide dismutase (ecSOD), a major form of vascular SOD. In mice, angiotensin II infusion (1.1 mg/kg for 7 days) increased systolic blood pressure from 107+/-3 to 152+/-9 mm Hg and caused a 3-fold increase in ecSOD, but there was no change in the cytosolic Cu/Zn SOD protein, as determined by Western blot analysis. This was associated with a similar increase in ecSOD mRNA as assessed by RNase protection assay and was prevented by losartan. Induction of ecSOD by angiotensin II was not due to hypertension alone, because hypertension caused by norepinephrine (5.6 mg. kg-1. d-1) had no effect on ecSOD. Similarly, exposure of mouse aortas to angiotensin II (100 nmol/L) in organoid culture increased ecSOD by approximately 2-fold. In the organoid culture, angiotensin II-induced upregulation of ecSOD was prevented by losartan (10 micromol/L) and PD985059 (30 micromol/L), a specific inhibitor of p42/44 MAP kinase kinase. Angiotensin II activates the NADH/NADPH oxidase; however, diphenyleneiodonium chloride (10 micromol/L), an inhibitor of this oxidase, did not prevent p42/44 MAP kinase phosphorylation or ecSOD induction by angiotensin II. Finally, in human aortic smooth muscle cells, angiotensin II moderately increased transcriptional rate (as assessed by nuclear run-on analysis) but markedly increased ecSOD mRNA stability. Thus, angiotensin II increases ecSOD expression independent of hypertension, and this increase involves both an increase in ecSOD transcription and stabilization of ecSOD mRNA. This effect of angiotensin II on ecSOD expression may modulate the oxidative state of the vessel wall in pathological processes in which the renin-angiotensin system is activated.
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PMID:Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. 1040 Sep 7

Endothelial dysfunction and remodeling of the vessel wall of large and small arteries is associated with hypertension and other risk factors for cardiovascular disease. These changes alter vascular function and mechanics, aggravate high blood pressure (BP), and may accelerate the progression of atherosclerosis. Activation of oxidative stress by angiotensin II is a key component of this process. Angiotensin II stimulates nicotinamide adenine dinucleotide phosphate (NADPH)/nicotinamide adenine dinucleotide (NADH) oxidase in endothelium, smooth muscle cells, and the adventitia of blood vessels to generate reactive oxygen species, leading to endothelial dysfunction, growth, and inflammation. Upregulation of endothelin-1, adhesion molecules, nuclear factor-kappaB, and other inflammatory mediators, as well as increased breakdown of nitric oxide and uncoupling of nitric oxide synthase, contribute to the progression of vascular disease and atherogenesis. Clinical studies in which treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) was used demonstrated correction of some of the changes in large and small arteries in hypertensive subjects, whereas identical BP lowering with beta-blockers had no effect on endothelial function. In experimental models of atherosclerosis, ARBs, including losartan potassium, valsartan, and olmesartan medoxomil, have demonstrated the ability to prevent the progression of atherosclerosis. This was in part associated with decreased expression of inflammatory mediators and improved endothelial function. Blockade of the renin-angiotensin-aldosterone system with ACE inhibitors or ARBs appears to blunt both the development and progression of vascular disease in both small and large vessels in experimental models and in humans beyond the effect of these agents on BP. This may help to explain the positive results of recently completed trials such as Heart Outcomes Prevention Evaluation (HOPE) and Losartan Intervention for Endpoint Reduction in Hypertension (LIFE).
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PMID:Beyond blood pressure: the endothelium and atherosclerosis progression. 1238 92

Activation of the renin-angiotensin system has been implicated in the development of hypertension in menopausal women. We investigated whether blood pressure is elevated and whether angiotensin II (Ang II)-induced vascular reactivity is increased in follitropin receptor knockout (FORKO) female mice. These mice are estrogen-deficient and have characteristics similar to postmenopausal women. Serum estradiol levels were significantly reduced in FORKO versus wild-type mice (1.4+/-0.2 versus 15+/-3 pg/mL, P<0.01). Blood pressure, measured by telemetry, was significantly increased in FORKO (120+/-2/92+/-2 mm Hg) compared with wild-type counterparts (110+/-1/85+/-2 mm Hg, P<0.05). Vascular dose responses to acetylcholine (endothelium-dependent dilation) and sodium nitroprusside (endothelium-independent dilation) were not different. Ang II-induced vasoconstriction was blunted in FORKO compared with wild-type mice (P<0.05). Media-to-lumen ratio was significantly increased in FORKO (6.2+/-0.5%) versus control mice (5.2+/-0.3%), indicating vascular remodeling. Aortic*O2- levels, NADH-inducible.O2- generation, and plasma levels of thiobarbituric acid reactive substances (TBARS), indexes of oxidative stress, were not significantly different between wild-type and FORKO mice. Vascular AT1 receptor content, assessed by immunoblotting, was reduced by 40% in FORKO compared with wild-type mice (P<0.01). This was associated with decreased circulating Ang II levels in FORKO versus control mice. These data indicate that FORKO mice have increased blood pressure, vascular remodeling, and attenuated vascular responses to Ang II. Our findings suggest that vascular Ang II signaling is downregulated in female FORKO mice and that Ang II may not play an important role in blood pressure elevation in this model of menopause-associated hypertension.
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PMID:Attenuated responses to angiotensin II in follitropin receptor knockout mice, a model of menopause-associated hypertension. 1288 94

The hypothesis that a high salt (HS) intake increases oxidative stress was investigated and was related to renal cortical expression of NAD(P)H oxidase and superoxide dismutase (SOD). 8-Isoprostane PGF(2alpha) and malonyldialdehyde were measured in groups (n = 6 to 8) of conscious rats during low-salt, normal-salt, or HS diets. NADPH- and NADH-stimulated superoxide anion (O(2)(.-)) generation was assessed by chemiluminescence, and expression of NAD(P)H oxidase and SOD were assessed with real-time PCR. Excretion of 8-isoprostane and malonyldialdehyde increased incrementally two- to threefold with salt intake (P < 0.001), whereas prostaglandin E(2) was unchanged. Renal cortical NADH- and NADPH-stimulable O(2)(.-) generation increased (P < 0.05) 30 to 40% with salt intake. Compared with low-salt diet, HS significantly (P < 0.005) increased renal cortical mRNA expression of gp91(phox) and p47(phox) and decreased expression of intracellular CuZn (IC)-SOD and mitochondrial (Mn)-SOD. Despite suppression of the renin-angiotensin system, salt loading enhances oxidative stress. This is accompanied by increased renal cortical NADH and NADPH oxidase activity and increased expression of gp91(phox) and p47(phox) and decreased IC- and Mn-SOD. Thus, salt intake enhances generation of O(2)(.-) accompanied by enhanced renal expression and activity of NAD(P)H oxidase with diminished renal expression of IC- and Mn-SOD.
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PMID:Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. 1456 87

Renal and cardiac benefits of renin-angiotensin system inhibition exceed blood pressure (BP) reduction and seem to involve mitochondrial function. It has been shown that RAS inhibition prevented mitochondrial dysfunction in spontaneously hypertensive rats (SHR) kidneys. Here, it is investigated whether a non-antihypertensive enalapril dose protects cardiac tissue and mitochondria function. Three-month-old SHR received water containing enalapril (10 mg/kg/day, SHR+Enal) or no additions (SHR-C) for 5 months. Wistar-Kyoto rats (WKY) were normotensive controls. At month 5, BP was similar in SHR+Enal and SHR-C. In SHR+Enal and WKY, heart weight and myocardial fibrosis were lower than in SHR-C. Matrix metalloprotease-2 activity was lower in SHR+Enal with respect to SHR-C and WKY. In SHR+Enal and WKY, NADH/cytochrome c oxidoreductase activity, eNOS protein and activity and mtNOS activity were higher and Mn-SOD activity was lower than in SHR-C. In summary, enalapril at a non-antihypertensive dose prevented cardiac hypertrophy and modifies parameters of cardiac mitochondrial dysfunction in SHR.
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PMID:Cardiac mitochondrial function and tissue remodelling are improved by a non-antihypertensive dose of enalapril in spontaneously hypertensive rats. 1929 28

The renin-angiotensin system plays a pivotal role in regulating blood pressure and is involved in the pathogenesis of kidney disorders and other diseases. Here, we report that the growth factor midkine is what we believe to be a novel regulator of the renin-angiotensin system. The hypertension induced in mice by 5/6 nephrectomy was accompanied by renal damage and elevated plasma angiotensin II levels and was ameliorated by an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker. Notably, ACE activity in the lung, midkine expression in the lung, and midkine levels in the plasma were all increased after 5/6 nephrectomy. Exposure to midkine protein enhanced ACE expression in primary cultured human lung microvascular endothelial cells. Furthermore, hypertension was not induced and renal damage was less severe in midkine-deficient mice. Supplemental administration of midkine protein to midkine-deficient mice restored ACE expression in the lung and hypertension after 5/6 nephrectomy. Oxidative stress might be involved in midkine expression, since expression of NADH/NADPH oxidase-1, -2, and -4 was induced in the lung after 5/6 nephrectomy. Indeed, the antioxidative reagent tempol reduced midkine expression and plasma angiotensin II levels and consequently ameliorated hypertension. These results suggest that midkine regulates the renin-angiotensin system and mediates the kidney-lung interaction after 5/6 nephrectomy.
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PMID:The growth factor midkine regulates the renin-angiotensin system in mice. 1945 97


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