Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The results issued from experimental models and randomized controlled clinical trials have shown that the more intense is the blockade of the renin-angiotensin system (RAS), the more effective is the prevention of target organ damage. Combined inhibition of the RAS is aimed at more complete blockade of the system through action at two different sites, angiotensin I converting enzyme (ACE) and AT1 receptors. This is achieved either by neutralizing the rise in renin and angiotensin (Ang) I, which follows the interruption of the Ang II-renin negative feed-back loop, or by directly antagonizing Ang II, whose synthesis is in part independent of the RAS. By comparison with higher doses of single site RAS blockers, a combination of an ACE inhibitor and an AT1 receptor antagonist block more effectively the RAS. After the demonstration of its synergistic or additive blood pressure lowering effects in sodium depleted normotensive subjects and animal models, combined blockade of the RAS was shown to be more efficient than single site RAS blockade: 1. in lowering blood pressure in hypertensive patients; 2. in lowering proteinuria and possibly retarding progression of renal failure in patients with diabetic and non-diabetic nephropathy; 3. finally, in improving left ventricular remodelling, cardiac function status and cardiovascular morbidity and mortality in patients with congestive heart failure. The advantage offered by combining two RAS blockers is to increase the beneficial effect of cardioprotection and nephroprotection which are currently demonstrated with the highest doses of an ACE inhibitor or an AT1 receptor antagonist.
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PMID:[Blockade of the renin-angiotensin system by a combination of ACE inhibitors and AT1 receptor antagonists]. 1549 22

Investigations conducted in medical centers worldwide and ours indicate that patients with chronic allograft nephropathy (CAN) will have short kidney graft survival when proteinuria and/or azotemia develop early, during the first post transplantation year. The analysis of published results suggests that angiotensin-converting enzyme (ACE) DD genotype represents unfavorable marker of rapid progression of chronic renal allograft dysfunction (CRAD). Differences of response to ACEi therapy in patients with chronic nephropathy of one's one or transplanted kidney could be explained by ACE genotype variety, where ACE DD is unfavorable genotype. Related factors influencing the ACEi therapy success in patients with particular ACE genotype are highly salt diet, interactions of genotype variety of all renin-angiotensin-aldosterone system (RAS) molecules, i.e. diversity in the ACE, angiotensinogen, AT1 receptor or aldosterone genotype, as well as differences of ACEi responses in patients with glomerular and tubulointerstitial kidney diseases. Retardation of chronic renal failure in patients with ACE DD genotype who developed chronic allograft nephropathy has been obtained with long-term ACEi treatment and restricted salt intake to 50 mmol Na+ per day. We consider that genotype investigation of RAS molecule, primarily of ACE genotype in recipient and kidney donor should be done before high-risk kidney transplantation.
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PMID:[The significance of angiotensin-converting enzyme inhibitors genotype for ACEi response in patients with chronic allograft nephropathy]. 1620 11

The aims of the present work were to determine whether a brief renin-angiotensin system blockade with AT1 receptor antagonist or angiotensin-converting enzyme inhibitor may provide long-lasting protection against hypertension and proteinuria in both young and adult Lyon hypertensive (LH) rats. Young pre-hypertensive Lyon hypertensive rats were orally treated with 5, 10, or 20 mg/kg/d of losartan, or with 0.4 mg/kg/d of perindopril from 3 to 12 weeks of age. Adult Lyon hypertensive rats were treated with 10 mg/kg/d of losartan, 0.4 mg/kg/d of perindopril, or a combination of both from 12 to 20 weeks of age. Telemetric blood pressure (BP) and urinary protein excretion were evaluated during and after treatment cessation. In young prehypertensive Lyon hypertensive rats, losartan fully prevented the hypertension and proteinuria; these effects were dose dependent and persisted long after treatment withdrawal. When renin-angiotensin system blockade was initiated in adult Lyon hypertensive rats with established hypertension, 10 mg/kg/d of losartan or 0.4 mg/kg/d of perindopril induced a significant regression in both blood pressure (15%-20%) and proteinuria (40%-50%) as did in young Lyon hypertensive rats; the combination treatment produced an additional effect only on blood pressure. After treatment cessation, a reduction in blood pressure persisted in all the pretreated adult Lyon hypertensive rats whereas the effect on proteinuria was less marked. In conclusion, whatever the blocker used, an early renin-angiotensin system blockade in prehypertensive Lyon hypertensive rats induces a durable prevention of hypertension and associated renal alterations. The similar renin-angiotensin system blockade in adult Lyon hypertensive rats provides a regression of hypertension and proteinuria, but the persistence of these beneficial effects is less pronounced than in young Lyon hypertensive rats, thus suggesting that the treatment with renin-angiotensin system blockers should be initiated as early as possible before the full expression of hypertension, to achieve the maximal long-lasting effects in mature stage.
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PMID:Blood pressure and proteinuria after cessation of a brief renin-angiotensin system blockade in young and adult Lyon hypertensive rats. 1630 96

Angiotensin II can induce oxidant stress by stimulating vascular superoxide production. Hypertension promotes mitochondrial function decline in brain, liver and heart. The aim of this study was to investigate whether a) hypertension is associated to kidney mitochondrial dysfunction, and b) angiotensin II blockade can reverse potential mitochondrial changes in hypertension. Four-month-old male spontaneously hypertensive rats (SHR) received drinking water containing candesartan (7.5 mg/kg/day, SHR+Cand), or no additions (SHR) for 4-months. Eight-month-old Wistar-Kyoto rats (WKY), that received water with no additions, were used as control. Systolic blood pressure, proteinuria, cortical glomerular area, and glomerular and tubulointerstitial alpha-smooth muscle actin labeling, were significantly higher, and creatinine clearance was significantly lower, in SHR relative to WKY and SHR+Cand. In SHR, kidney mitochondria membrane potential, and nitric oxide synthase and cytochrome oxidase activities were significantly lower than in WKY and SHR+Cand. In SHR, mitochondrial hydrogen peroxide production was significantly higher than in WKY and SHR+Cand. The results suggest that, in hypertension, increased mitochondrial oxidant production may mediate kidney mitochondria dysfunction. Candesartan preserved mitochondrial function, probably favoring the maintenance of adequate cellular and tissue function in the kidney. The known renal protective effects of candesartan in hypertension may be related to the improvement of mitochondrial function. This may be an additional or alternative explanation for some of the beneficial effects of AT1 receptor antagonists.
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PMID:Angiotensin II blockade improves mitochondrial function in spontaneously hypertensive rats. 1630 82

The level of proteinuria is one of the most important risk factors for progressive renal function loss in renal diseases. Any therapeutic measure that reduces proteinuria will slow or halt the progression of proteinuric nephropathies. Blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors or AT1-receptor antagonists (ARA) is currently the most powerful available antiproteinuric treatment. Recent investigations point out that blockade of RAAS at other levels (e.g., aldosterone or renin antagonists) could also induce a significant decrease in proteinuria. Because angiotensin II is also generated from angiotensin I by enzymes other than ACE, ARA would provide a more effective blockade of angiotensin II; however, ACE inhibition increases plasma levels of substances such as bradykinin and N-acetyl-seryl-aspartyl-lysyl-proline, which have strong antifibrotic properties. These differential effects of ACE inhibitors and ARA are the rationale for combined administration of both agents, which in clinical studies has demonstrated a significantly higher antiproteinuric and renoprotective effect than by either drug alone. Salt and protein restriction, as well as cautious use of diuretics, can also increase the antiproteinuric effect of RAAS blockade. Treatment with statins or other lipid-lowering agents leads to reduction in proteinuria levels, as some meta-analyses have demonstrated. Smoking is associated with an increased risk for the appearance of proteinuria, so cessation of smoking should be mandatory in proteinuric renal diseases. Recent studies have highlighted an epidemic increase of obesity-related proteinuric glomerulopathies; weight loss is effective not only in this condition, but also in overweight patients with proteinuric nephropathies of other etiologies.
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PMID:Therapeutic measures in proteinuric nephropathy. 1633 67

Mitochondrial dysfunction is associated with cardiovascular damage; however, data on a possible association with kidney damage are scarce. Here, we aimed at investigating whether 1) kidney impairment is related to mitochondrial dysfunction; and 2) ANG II blockade, compared with Ca2+ channel blockade, can reverse potential mitochondrial changes in hypertension. Eight-week-old male spontaneously hypertensive rats (SHR) received water containing losartan (40 mg.kg-1.day-1, SHR+Los), amlodipine (3 mg.kg-1.day-1, SHR+Amlo), or no additions (SHR) for 6 mo. Wistar-Kyoto rats (WKY) were normotensive controls. Glomerular and tubulointerstitial damage, systolic blood pressure, and proteinuria were higher, and creatinine clearance was lower in SHR vs. SHR+Los and WKY. In SHR+Amlo, blood pressure was similar to WKY, kidney function was similar to SHR, and renal lesions were lower than in SHR, but higher than in SHR+Los. In kidney mitochondria from SHR and SHR+Amlo, membrane potential, nitric oxide synthase, manganese-superoxide dismutase and cytochrome oxidase activities, and uncoupling protein-2 content were lower than in SHR+Los and WKY. In SHR and SHR+Amlo, mitochondrial H2O2 production was higher than in SHR+Los and WKY. Renal glutathione content was lower in SHR+Amlo relative to SHR, SHR+Los, and WKY. In SHR and SHR+Amlo, glutathione was relatively more oxidized than in SHR+Los and WKY. Tubulointerstitial alpha-smooth muscle actin labeling was inversely related to manganese-superoxide dismutase activity and uncoupling protein-2 content. These findings suggest that oxidant stress is associated with renal mitochondrial dysfunction in SHR. The mitochondrial-antioxidant actions of losartan may be an additional or alternative way to explain some of the beneficial effects of AT1-receptor antagonists.
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PMID:Renal mitochondrial dysfunction in spontaneously hypertensive rats is attenuated by losartan but not by amlodipine. 1641 Apr 2

The development of angiotensin receptor blockers (ARBs) has resulted in effective oral treatment for hypertension. One of the most recent members of this therapeutic class is olmesartan medoxomil (OM). The active metabolite, olmesartan, produces insurmountable AT1 receptor blockade and dose-dependently reduces BP. In both experimental and clinical studies, ARBs have been shown to exert renoprotective effects in addition to antihypertensive activity. In an SHR model of hypertensive renal injury, OM (3.0 and 10.0 mg/kg/day) dose-dependently reduced BP but also reduced urinary protein excretion by 65% and 75%, respectively (P < 0.05). Similar doses of OM, in a DOCA-salt hypertensive rat model, did not affect BP but reduced urinary protein excretion by 26% and 39% when compared to control hypertensive animals (P < 0.05). Hypertension is a major pathophysiological determinant of progressive arterial damage that can accelerate the development of diabetic nephropathy. At doses of 0.6 and 6.0 mg/kg/day, OM significantly reduces hypertension associated with type 2 diabetes. These doses of OM reduced BP and dose-dependently reduced proteinuria 31% and 76%, respectively, in hypertensive ZDF rats (P < 0.01). OM also reduced renocortical and renomedulla injury by 19% and 50% at doses of 0.6 and 6.0 mg/kg/day. The glomerular sclerosis index (GSI) was also reduced by 25% and 37% (P < 0.05). Thus, OM improves both functional and morphologic damage associated with diabetic nephropathy. These studies demonstrate that OM, a potent ARB, dose-dependently reduces BP and also provides a dose-related nephroprotective effect in animal models of diabetes. These studies show that the antihypertensive affect of OM is renoprotective but suggest that these renal benefits may also occur independently from a reduction in BP. A further evaluation of the effects of OM in diabetes is warranted.
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PMID:The angiotensin-II (AT-II) receptor blocker olmesartan reduces renal damage in animal models of hypertension and diabetes. 1641 56

Hypertension in pregnancy is one of the main causes of maternal, fetal and newborn morbidity and mortality in civilised countries. Current recommendations of the European Society for Hypertension prefer definition of hypertension in pregnancy based on absolute values of blood pressure, i.e. systolic blood pressure > or = 140 mm Hg or diastolic blood pressure > or = 90 mm Hg. The most important task of classification of hypertension in pregnancy is to distinguish whether hypertension comes before pregnancy (the so called pre-existing hypertension) or whether it is a pregnancy-induced condition (the so called gestational hypertension). Pre-existing hypertension is diagnosed either before pregnancy or within the first 20 weeks of pregnancy. Gestational hypertension is characterised with poor blood circulation in many body organs, higher value of blood pressure usually being just one of the characteristic features. Non-pharmacological treatment of hypertension must be considered in pregnant women with systolic blood pressure 140-150 mm Hg or diastolic blood pressure 90-99 mm Hg. Salt restriction is not recommended, as well as weight reduction in obese women. Systolic blood pressure > or = 170 mm Hg or diastolic blood pressure > or = 110 mm Hg in pregnant women must be considered serious condition necessitating hospitalisation. Pharmacological therapy should include labetalol i.v. or metyldopa or nifedipin administered orally. Intravenous administration of dihydralazine is no longer a therapy of choice, for its use is connected with increased occurrence of adverse effects. The threshold values for commencement of anti-hypertension therapy are systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg in females with gestational hypertension without proteinuria or with pre-existing hypertension before commencement of 28th week of pregnancy. Drug administration to reduce hypertension is instituted after reaching the same threshold values in females with gestational hypertension and proteinuria or after occurrence of the symptoms any time during pregnancy, with the same threshold values of blood pressure in the case of pre-existing hypertension at the presence of accompanying diseases or organ malfunction and further in the case of pre-existing hypertension and gestational hypertension. In other cases drug treatment of hypertension is recommended at systolic blood pressure values of 150 mm Hg or diastolic blood pressure values of 95 mm Hg. Unless serious hypertension is involved, the drugs of choice include metyldope, labetalol, calcium channel blockers and beta-blockers. Calcium channel blockers are considered safe, unless administered concurrently with magnesium sulphate (risk of hypotension in the case of potential synergism). ACE inhibitors and angiotensine blockers II (AT1-blockers) are contraindicated in pregnancy. Treatment with diuretics is not substantiated, unless oliguria is present. I.v. magnesium sulphate is recommended for prevention of eclampsia and spasm treatment.
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PMID:[Hypertension in pregnancy]. 1672 58

The effectiveness of antisense (AS) phosphorothioated oligodeoxynucleotides (AS-ODN) targeted to the angiotensin (ANG) type 1 (AT1) receptor, was studies in Ren-2 transgenic rats (TGR), whose ANG II-dependent hypertension can be attributed to the insertion of a single mouse renin gene. Our results show that a single intraarterial bolus injection of AT1-AS in 30-day-old rats results in a prolonged lowering of systolic blood pressure (SBP) for a period of 18 days with an average difference in SBP of 30 mm Hg between AS-treated and untreated TGR. No effect of AS therapy on SBP has been observed in control HanSD animals. However, at the end of the experiment, i.e. on day 100 of age, there were no differences in mean arterial pressure, proteinuria or cardiac hypertrophy between AS-treated and untreated TGR. Thus, no persistent effect of this therapy was observed after a single bolus injection. Collectively, the data show a prolonged antihypertensive effect of AT1 receptor antisense oligonucleotides during the developmental phase of hypertension in TGR when applied as a single treatment in prehypertensive animals which, however, does not persist up to the maintenance phase of hypertension in adulthood.
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PMID:AT1 receptor antisense therapy transiently lowers blood pressure in Ren-2 transgenic rats. 1752 68

The renin-angiotensin-aldosterone system (RAAS) plays an important part in the pathogenesis of arterial hypertension and the complications it causes in organs (the heart, the circulatory system, the brain, the kidneys), heart failure and kidney diseases. Materials that block the most upstream point of the RAAS cascade (ACE inhibitors - ACEI, AT1,-receptor (AT1R) blockers, aldosterone receptor blockers) have greatly expanded our options in the treatment and primary and secondary prevention of cardiovascular and renal diseases. ACEI and AT1R blockers interrupt the normal feedback provided by the release of renin into the circulatory system from the kidneys. After they are applied the reactive increase in active circulating renin leads to increased creation of angiotensin I and angiotensin II and the subsequent return of aldosterone secretions to pre-treatment values ("escape" phenomenon). The possible negative effect of these intermediary products of an incomplete blockade of RAAS on organ complications lead to an effort to develop a material that could block the renin-angiotensin cascade at its first stage--i.e. a renin blocker. The first efforts with renin antibodies or peptide analogues of renin prosegments failed to satisify the basic requirements for long-term medication--effectiveness when used orally. In recent years the first non-peptidic, oral renin ihibitor providing sustained effects has been developed, aliskiren fumarate. Aliskiren reduces BP depending on the dose (50-300 mg/day) in monotherapy or in combination with hydrochlorothiazide. Aliskiren lowers plasma renin activity (PRA) and neutralises the activation of the RAAS triggered by hydrochlorothiazide. Ambulatory BP monitoring has shown that taking the medicine once a day has a 24-hour effect and its continued residence in the kidneys suggests renoprotective effects. The compound is in the third stage of clinical tests as a monotherapy or in combination for the treatment of hypertension. It has also been shown to have an influence on the regression of cardiac hypertrophy (Aliskiren in Left-Ventricular Hypertrophy trial - ALLAY), the treatment of heart failure (Aliskiren Observation of Heart Failure Treatment trial - ALOFT) and diabetic (Aliskiren in the Evaluation of Proteinuria in Diabetes trial - AVOID). In April 206, the FDA permitted the use of aliskiren in the USA for the treatment of high BP and it is currently undergoing testing in Europe. The renin inhibitor has minimal undesirable side effects, like AT1-receptor blockers. The slightly lower effectiveness ofaliskiren than AT1-receptor blockers in reducing BP is caused by the fact that it does not block bradykinins. It is recommended as a monotherapy for clinical use or in combination with other antihypertensive medicines for conditions with high levels of PRA including its rise after diuretics, ACEI and AT1-receptor blockers. Aliskiren could therefore be used primarily with young patients, Caucasians, persons with ACEI intolerance, and also in diseases where angiotensin II is involved in the pathogenesis and the secondary prevention of cardiovascular disease. It is also safe for persons with concurrent renal problems, because it is mainly removed by the liver without great interference with other materials. Like ACEI, the renin inhibitor has a vasodilatory effect which could potentially improve the elasticity of arteries. The medicine has the same limitations and contraindications as ACEI and AT1R blockers, such as pregnancy and bilateral renal artery stenosis. A definitive assessment of the benefit of this new class of medicines and its broad application in the treatment of cardiovascular and other diseases will require demonstration of its long-term effect on morbidity and mortality, as well as comparison with other RAAS blockers in long clinical studies, which represent research programmes lasting another 7 to 8 years.
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PMID:[Does the rennin inhibitor aliskiren offer promising novel opportunities in the treatment of cardiovascular diseases?]. 1757 67


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