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)

Aldosterone has pro-fibrotic properties and is a potential target for additional intervention in patients with chronic renal disease showing resistance to therapy during treatment with angiotensin-converting enzyme inhibitors (ACEi). Combining ACEi and aldosterone receptor blockade (aldoRB) in proteinuric renal disease reduces proteinuria, but effects on proteinuria-induced renal damage are unknown. We studied the effect of ACEi/aldoRB in adriamycin nephrosis (AN). Six weeks after injection of adriamycin in Wistar rats, randomized treatment with vehicle (VEH, n=8), aldoRB (n=12), ACEi (n=10), or a combination of ACEi/aldoRB (n=14) was given for 12 weeks. Healthy rats served as controls (n=6). Renal damage was quantified by markers of tubular injury (osteopontin (OPN) and kidney injury molecule-1 (Kim-1)), pre-fibrotic lesions (alpha-smooth muscle actin (SMA)), interstitial fibrosis (IF), and focal glomerulosclerosis (FGS). In AN animals, proteinuria was increased compared with controls. ACEi and ACEi/aldoRB significantly reduced proteinuria compared with VEH, whereas aldoRB monotherapy was without effect. Blood pressure was reduced in ACEi and ACEi/aldoRB compared with VEH and aldoRB. OPN and Kim-1 were increased in AN animals, but significantly reduced by ACEi/aldoRB. Treatment with ACEi and ACEi/aldoRB prevented an increase of SMA, IF, and FGS. In conclusion, ACEi/aldoRB effectively reduced proteinuria and markers of tubular injury and prevented renal damage in this rat model of chronic proteinuria-induced renal damage.
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PMID:Effect of combining ACE inhibition with aldosterone blockade on proteinuria and renal damage in experimental nephrosis. 1794 59

Despite progress in recent years in the prevention, detection, and treatment of high blood pressure (BP), hypertension remains an important public health challenge. Hypertension affects approximately 1 billion individuals worldwide. High BP is associated with an increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and end-stage renal disease; it also has a negative impact on the quality of life. Hypertension cannot be eliminated because there are no vaccines to prevent the development of hypertension, but, its incidence can be decreased by reducing the risk factors for its development, which include obesity, high dietary intake of fat and sodium and low intake of potassium, physical inactivity, smoking, and excessive alcohol intake. For established hypertension, efforts are to be directed to control BP by lifestyle modification (LSM). However, if BP cannot be adequately controlled with LSM, then pharmacotherapy can be instituted along with LSM. Normalization of BP reduces cardiovascular risk (for cardiovascular death, myocardial infarction, and cardiac arrest), provides renoprotection (prevention of the onset or slowing of proteinuria and progression of renal dysfunction to end-stage renal disease in patients with hypertension, diabetes mellitus types 1 and 2, and chronic renal disease), and decreases the risk of cerebrovascular events (stroke and cognition impairment), as has been amply demonstrated by a large number of randomized clinical trials. In spite of the availability of more than 75 antihypertensive agents in 9 classes, BP control in the general population is at best inadequate. Therefore, antihypertensive therapy in the future or near future should be directed toward improving BP control in treated hypertensive patients with the available drugs by using the right combinations at optimum doses, individually tailored gene-polymorphism directed therapy, or development of new modalities such as gene therapy and vaccines. Several studies have shown that BP can be reduced by lifestyle/behavior modification. Although, the reductions appear to be trivial, even small reductions in systolic BP (for example, 3-5 mm Hg) produce dramatic reduction in adverse cardiac events and stroke. On the basis of the results of clinical and clinical/observational studies, it has been recommended that more emphasis be placed on lifestyle/behavior modification (obesity, high dietary intake of fat and sodium, physical inactivity, smoking, excessive alcohol intake, low dietary potassium intake) to control BP and also to improve the efficacy of pharmacologic treatment of high BP. New classes of antihypertensive drugs and new compounds in the established drug classes are likely to widen the armamentarium available to combat hypertension. These include the aldosterone receptor blockers, vasodilator beta-blockers, renin inhibitors, endothelin receptor antagonists, and dual endopeptidase inhibitors. The use of fixed-dose combination drug therapy is likely to increase. There is a conceptual possibility that gene therapy may yield long-lasting antihypertensive effects by influencing the genes associated with hypertension. But, the treatment of human essential hypertension requires sustained over-expression of genes. Some of the challenging tasks for successful gene therapy that need to be mastered include identification of target genes, ideal gene transfer vector, precise delivery of genes into the required site (target), efficient transfer of genes into the cells of the target, and prompt assessment of gene expression over time. Targeting the RAS by antisense gene therapy appears to be a viable strategy for the long-term control of hypertension. Several problems that are encountered in the delivery of gene therapy include 1) low efficiency for gene transfer into vascular cells; 2) a lack of selectivity; 3) problem in determining how to prolong and control transgene expression or antisense inhibition; and 4) difficulty in minimizing the adverse effects of viral or nonviral vectors. In spite of the hurdles that face gene therapy administration in humans, studies in animals indicate that gene therapy may be feasible in treating human hypertension, albeit not in the near future. DNA testing for genetic polymorphism and determining the genotype of a patient may predict response to a certain class of antihypertensive agent and thus optimize therapy in individual patients. In this regard, there are some studies that report the effectiveness of antihypertensive therapy based upon the genotype of selected patients. Treatment of human hypertension with vaccines is feasible but is not likely to be available in the near future.
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PMID:The future of antihypertensive treatment. 1741 79

The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine, and NADPH oxidase (NOX) subunits (gp91(phox) recently renamed NOX2, p22(phox), Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.
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PMID:Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. 1749 96

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

Studies have shown that dual therapy with angiotensin-converting enzyme inhibitors (ACEI) and either angiotensin II receptor blockers or aldosterone receptor antagonists is more effective in reducing proteinuria than either agent used alone. The questions that remain are as follows: (1) Which of these agents should be used as dual therapy with the ACEI? (2) Does a higher level of blockade of the renin-angiotensin-aldosterone system with triple therapy offer an advantage over dual blockade? A 3-mo randomized, double-blind, placebo-controlled study was performed in 41 patients with proteinuria >1.5 g/d. Four treatment groups were compared: (1) Ramipril + spironolactone placebo + irbesartan placebo, (2) ramipril + irbesartan + spironolactone placebo, (3) ramipril + irbesartan placebo + spironolactone, and (4) ramipril + irbesartan + spironolactone. The percentage change in protein excretion differed according to treatment arm (ANOVA: F(3,35) = 8.6, P < 0.001). Pair-wise comparison showed that greater reduction in protein excretion occurred in treatment regimens that incorporated spironolactone. The reduction in proteinuria at 3 mo was as follows: Group 1, 1.4%; group 2, 15.7%; group 3, 42.0%; and group 4, 48.2%. The reduction in proteinuria among patients who were taking spironolactone-containing regimens was sustained at 6 and 12 mo. This study suggests that aldosterone receptor blockade offers a valuable adjuvant treatment when used with ACEI therapy for the reduction of proteinuria. Results suggest no advantage of triple blockade over dual blockade of the renin-angiotensin-aldosterone system to reduce proteinuria.
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PMID:Double-blind, placebo-controlled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker. 1769 14

The contribution of elevated aldosterone to the pathogenesis of malignant, ANG II-dependent hypertension remains uncertain. Therefore, we examined whether chronic mineralocorticoid receptor blockade attenuates the development of malignant hypertension in transgenic rats (TGRs) with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Systolic blood pressure (SBP) was measured by radiotelemetry in male TGRs in three groups: 1) control (n = 9), 2) hypertensives (HT; n = 8), and 3) hypertensives + spironolactone (11 mg.kg(-1).day(-1) sc; HTS; n = 8). Malignant hypertension was induced with dietary indole-3-carbinol (0.3%) for 10 days. Metabolic measurements were taken at the beginning of the study and at days 2 and 9. HT exhibited elevated SBP (125 +/- 3 vs. 187 +/- 5 mmHg), plasma renin activity (5 +/- 1 vs. 29 +/- 10 ng ANG I.ml(-1).h(-1)), plasma ANG II (175 +/- 39 vs. 611 +/- 74 fmol/ml), and plasma aldosterone (0.31 +/- 0.04 vs. 5.42 +/- 1.02 nmol/l). Urinary aldosterone excretion increased 5.5-fold by day 2 and an additional 90% by day 9. HT was associated with a 1.8-fold increase in proteinuria by day 9 that was alleviated by treatment with spironolactone (25 +/- 5 vs. 13 +/- 3 mg/day), suggesting that aldosterone contributes to the renal damage observed in malignant hypertension. Urinary Na+ excretion was decreased 76% on day 2, despite a sixfold increase in urinary aldosterone excretion. Decrease in urinary Na+ excretion on day 2 in HT suggests that Na+ reabsorption was increased in response to the increase in aldosterone; however, the lack of a change in SBP between HT and HTS suggests that mechanisms independent of aldosterone stimulation make a greater contribution to the maintenance of elevated arterial pressure in malignant hypertension in Cyp1a1-Ren2 transgenic rats.
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PMID:Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats. 1771 65

Aldosterone is implicated in the pathogenesis of proteinuria and chronic kidney disease. We previously demonstrated the contribution of elevated serum aldosterone in the early nephropathy of SHR/NDmcr-cp (SHR/cp), a rat model of metabolic syndrome. In the present study, we investigated the effect of salt loading on renal damage in SHR/cps and explored the underlying mechanisms. SHR/cps fed a high-sodium diet for 4 weeks developed severe hypertension, massive proteinuria, and advanced renal lesions. High salt also worsened glomerular podocyte impairment. Surprisingly, selective mineralocorticoid receptor (MR) antagonist eplerenone dramatically ameliorated the salt-induced proteinuria and renal injury in SHR/cps. Although salt loading reduced circulating aldosterone, it increased nuclear MR and expression of aldosterone effector kinase Sgk1 in the kidney. Gene expressions of transforming growth factor-beta1 and plasminogen activator inhibitor-1 were also enhanced in the kidneys of salt-loaded SHR/cps, and eplerenone completely inhibited these injury markers. To clarify the discrepancy between decreased aldosterone and enhanced MR signaling by salt, we further investigated the role of oxidative stress, a putative key factor mediating salt-induced tissue damage. Interestingly, antioxidant Tempol attenuated the salt-evoked MR upregulation and Sgk1 induction and alleviated proteinuria and renal histological abnormalities, suggesting the involvement of oxidative stress in salt-induced MR activation. MR activation by salt was not attributed to increased serum corticosterone or reduced 11beta-hydroxysteroid dehydrogenase type 2 activity. In conclusion, sodium loading exacerbated proteinuria and renal injury in metabolic syndrome rats. Salt reduced circulating aldosterone but caused renal MR activation at least partially via induction of oxidative stress, and eplerenone effectively improved the nephropathy.
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PMID:Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress. 1792 84

Aldosterone is traditionally viewed as a hormone regulating electrolyte and blood pressure homeostasis by acting on the distal nephron. Accumulating evidence suggests that aldosterone also plays pathogenetic roles in cardiovascular and renal injury. For example, aldosterone is a potent inducer of proteinuria. We demonstrated that podocyte injury underlies the pathogenesis of proteinuria in aldosterone-infused rats on a high salt diet. Mineralocorticoid receptor was detected in the podocytes in vivo and in vitro, and aldosterone caused induction of its effector kinase Sgk1, activation of NADPH oxidase and generation of reactive oxygen species. Selective aldosterone blocker eplerenone, as well as antioxidant tempol, ameliorated aldosterone-induced podocyte injury and proteinuria. Aldosterone was also involved in the podocyte damage and proteinuria of metabolic syndrome model SHR/NDmcr-cp. Adipocyte-derived aldosterone releasing factors were suggested to contribute to the aldosterone excess of this model. Furthermore, high salt diet markedly worsened the renal injury of SHR/NDmcr-cp. Although salt lowered serum aldosterone levels, it caused MR activation in the kidney. Accordingly, eplerenone dramatically improved the salt-evoked nephropathy. Taken together, aldosterone blockers can be an excellent therapeutic strategy for the treatment of podocyte injury, proteinuria, and cardiovascular and renal complications, not only in high aldosterone states but also in patients with activated MR signaling in the target tissue, whose circulating aldosterone level is not necessarily high. Addition of aldosterone blockers in patients treated with ACEIs or ARBs are also promising, because of "aldosterone breakthrough" phenomenon. Careful monitoring of hyperkalemia is necessary, especially in patients with impaired renal function.
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PMID:Aldosterone and glomerular podocyte injury. 1831 76

The blockade of the renin-angiotensin-aldosterone system (RAAS) is helpful in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and diabetic nephropathy. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors, an aldosterone receptor antagonist and/or a direct inhibitor of renin such as aliskiren. Various studies have demonstrated that a dual or even triple RAAS inhibition may offer a better cardiorenal protection, in refractory congestive heart failure and in nephropathy with proteinuria. However, in the ONTARGET study, the dual inhibition with ramipril plus telmisartan did not provide any additional benefit compared to ramipril alone in high-risk cardiovascular patients, but showed a worse tolerance profile.
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PMID:[What is the purpose of dual or triple inhibition of the renin-angiotensin-aldosterone system?]. 1881 62

There is increasing evidence indicating the roles of aldosterone and mineralocorticoid receptor (MR) in the pathogenesis of renal injury. In rats, chronic treatment with aldosterone and salt results in severe proteinuria and renal tissue injury, characterized by glomerulosclerosis and tubulointerstitial fibrosis. Aldosterone-induced renal tissue injury is associated with increases in reactive oxygen species (ROS) levels and activation of mitogen-activated protein kinases (MAPKs) or Rho-kinase. Treatment with a selective MR antagonist, eplerenone, prevents aldosterone-induced increases in ROS levels and MAPK activity and ameliorates renal injury. In vitro studies have revealed that MR is highly expressed in glomerular mesangial cells (RMCs), podocytes, and renal interstitial fibroblasts. In these renal cells, aldosterone induces cellular injury through NADPH oxidase-dependent ROS production and activation of MAPKs or Rho-kinase. Such aldosterone-induced renal cellular injury is markedly attenuated by treatment with eplerenone. These data suggest that aldosterone induces renal injury via activation of MR through mechanisms that cannot be simply explained by changes in blood pressure. In this review, we summarized recent findings on the roles of aldosterone and MR in the pathogenesis of renal injury with particular emphasis on potential underlying mechanisms.
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PMID:Possible underlying mechanisms responsible for aldosterone and mineralocorticoid receptor-dependent renal injury. 1905 24


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