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)

Angiotensin-converting enzyme inhibitors and aldosterone receptor antagonists ameliorate malignant nephrosclerotic lesions of thrombotic microangiopathy in salt-loaded, stroke-prone, spontaneously hypertensive rats (SHRSP) without controlling hypertension. This suggests that angiotensin II (Ang II) and/or aldosterone (ALDO) plays a critical role in renal injury in this model. For evaluating their relative roles in the pathogenesis of thrombotic microangiopathy, SHRSP were adrenalectomized and infused with vehicle, Ang II, or ALDO or were sham-operated for adrenalectomy (SHAM). Saline-drinking rats were assigned to one of four groups: SHAM, adrenalectomy, adrenalectomy + Ang II (25 ng/min, subcutaneously), or adrenalectomy + ALDO (40 micro g/kg per d, subcutaneously). All SHRSP received dexamethasone (12 micro g/kg per d, subcutaneously). Adrenalectomy did not show changes in body weight, plasma creatinine, sodium and potassium, and daily urinary sodium and potassium excretion; did not prevent hypertension but prevented proteinuria (12 +/- 1 versus 49 +/- 3 mg/d; P < 0.01); and abrogated thrombotic microangiopathy and decreased plasma aldosterone (<16 versus 710 +/- 91 pg/ml; P < 0.001) compared with SHAM. Systolic BP in adrenalectomy + Ang II and adrenalectomy + ALDO (238 +/- 8 and 241 +/- 9 mmHg, respectively) was similar to SHAM. Despite Ang II infusion, proteinuria (17 +/- 9 mg/d) and thrombotic microangiopathy and plasma aldosterone (18 +/- 18 pg/ml) remained low but daily urinary excretion of sodium and potassium were not different from adrenalectomy + ALDO. Adrenalectomy + ALDO showed plasma aldosterone levels of 735 +/- 147 pg/ml; plasma potassium was lower; plasma creatinine and proteinuria (78 +/- 7 mg/d) were greater and thrombotic microangiopathy lesions were comparable to SHAM. These results demonstrate a pivotal role for aldosterone in the development of thrombotic microangiopathy, independent of hypertension.
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PMID:Aldosterone plays a pivotal role in the pathogenesis of thrombotic microangiopathy in SHRSP. 1287 52

In view of the ongoing controversy of cardiorenal safety of selective COX-2 inhibitors (coxibs), the present study was designed to examine the effects of 2 different coxibs, celecoxib and rofecoxib, compared with a traditional NSAID, diclofenac, and placebo on renal morphology and function in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl-enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib), or placebo was added to chow from weeks 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. Renal cortex mRNA was isolated for determination of COX-2, eNOS, and CRP mRNA by real-time reverse-transcriptase polymerase chain reaction. Untreated hypertensive animals showed glomerular injury including collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops, and an especially high grade of glomerulosclerosis (P<0.05 versus DR-placebo) and CD8-positive and ED1-positive cells (P<0.01 versus DR-placebo), which was improved by celecoxib but not by diclofenac and rofecoxib. C-reactive protein mRNA in renal cortex was increased in DS-placebo animals (P<0.05 versus DR-placebo) and normalized by celecoxib (P<0.05 versus DS-placebo), whereas eNOS mRNA was decreased in the DS-rofecoxib group (P<0.05 versus DR-placebo, DS-celecoxib, and DS-diclofenac). Proteinuria was observed in hypertensive animals (P<0.0001 versus DR-placebo), increased by rofecoxib (P<0.05 versus DS-placebo), and normalized by celecoxib (P=0.0015 versus DS-placebo). This head-to-head comparison of selective and nonselective COX inhibitors demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertension.
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PMID:Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension. 1562 40

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

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

Individuals with elevated blood pressure are at increased risk for cardiovascular events and death. Almost 50% of essential hypertension is salt-sensitive, this characteristic increases and becomes more prevalent with age. Salt sensitivity has been linked to an increased risk for the development of left ventricular hypertrophy, proteinuria, and a blunted nocturnal decline in blood pressure ("non-dipping"). Salt sensitivity implies an alteration in the relation between arterial pressure and sodium excretion or "pressure natriuresis". The development of salt-sensitive hypertension is proposed to occur in three phases. In the first phase, the kidney is structurally normal, and sodium is excreted normally. However, the kidney may be exposed to various stimuli that result in renal vasoconstriction. In the second phase, subtle renal injury develops, impairing sodium excretion and leading to an increase in blood pressure. In the third phase, the kidneys equilibrate at a higher blood pressure, allowing them to resume normal sodium handling. Other mechanisms, such as primary tubulointerstitial disease, genetic alterations in sodium regulation and excretion, or a congenital reduction in nephron number that limits sodium filtration are important in the development of salt-sensitive hypertension.
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PMID:[Salt-sensitive hypertension]. 1701 93

Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of alpha-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis.
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PMID:Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. 1739 57

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

Metabolic syndrome, which is caused by obesity, is now a global pandemic. Metabolic syndrome is an aggregation of hypertension, diabetes and dyslipidaemia. Insulin resistance is a key factor in the development of these components of metabolic syndrome. Concerning the mechanism for the development of hypertension in metabolic syndrome, the lack of insulin resistance in the kidney increases sodium reabsorption by hyperinsulinaemia, leading to sodium retention in the body, and resultant salt-sensitive hypertension. Moreover, hyperaldosteronism, which is caused by adipocyte-derived aldosterone-releasing factors, induces not only salt-sensitive hypertension, but also proteinuria in obese hypertensive rats. Salt loading markedly aggravates proteinuria and induces cardiac diastolic dysfunction in obese hypertensive rats, suggesting that salt and aldosterone exert unfavourable synergistic actions on the cardiovascular system, possibly through the overproduction of oxidative stress. In turn, reactive oxygen species (ROS), which are induced by adipokines such as tumour necrosis factor-alpha, non-esterified fatty acids, angiotensinogen etc., can activate the mineralocorticoid (MR) receptor, in an aldosterone-independent fashion. Therefore, aldosterone/MR activation plays a key role not only in the development of salt-sensitive hypertension, but also in cardiovascular injury in metabolic syndrome, possibly through its function as a feed-forward system.
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PMID:Aldosterone in salt-sensitive hypertension and metabolic syndrome. 1843 32

This study examined the genetic basis of hypertension and renal disease in Dahl SS/Mcwi (Dahl Salt-Sensitive) rats using a complete chromosome substitution panel of consomic rats in which each of the 20 autosomes and the X and Y chromosomes were individually transferred from the Brown Norway (BN) rat onto the Dahl SS/Mcwi genetic background. Male and female rats of each of the two parental and 22 consomic strains (10-12 rats/group) were fed a high-salt (8.0% NaCl) diet for 3 wk. Mean arterial blood pressure rose by 60 mmHg and urinary protein and albumin excretion increased 3- and 20-fold, respectively, in male SS/Mcwi rats compared with BN controls. Substitution of chromosomes 1, 5, 7, 8, 13, or 18 from the BN onto the SS/Mcwi background attenuated the development of hypertension, proteinuria, and albuminuria in male rats. In female rats, substitution of chromosomes 1 and 5 also decreased blood pressure, protein excretion, and albumin excretion. These studies also identified several chromosomes in male (6, 11, Y) and female (4, 6, 11, 19, 20) rats that reduced albuminuria without altering blood pressure. These data indicate that genes contributing to salt-sensitive hypertension are found on multiple chromosomes of the Dahl SS/Mcwi rat. Furthermore, this consomic rat panel provides a stable genetic platform that can facilitate further gene mapping by either linkage studies or the breeding of congenic and subcongenic rats.
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PMID:Chromosome substitution reveals the genetic basis of Dahl salt-sensitive hypertension and renal disease. 1865 78

The relation of salt to hypertension and kidney disease had been well known at the turn of the last century, but the importance of salt has been grossly neglected more recently. There is a close link between salt intake and hypertension, as well as partially blood pressure-independent target organ damage including renal disease. In the general population, high salt intake is associated with hypertension and cardiovascular events. Salt loading also increases albuminuria in individuals without primary renal disease and raises excretion of albumin and protein in patients with renal disease. It aggravates proteinuria and glomerulosclerosis and accelerates progression in most animal models of renal damage. The effect of salt restriction cannot be reproduced by treatment with diuretics. Inappropriate increase of intrarenal angiotensin II and increased reactive oxygen species are the major culprits responsible for salt-related renal damage.
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PMID:Role of sodium intake in the progression of chronic kidney disease. 1912 73


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