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)

Diabetic nephropathy has become the single most important cause of endstage renal failure in most countries of the Western world. Against this background, the role of the renin-angiotensin system (RAS) and its blockade command considerable interest. In diabetic patients and in diabetic animals, the circulating components of the RAS are suppressed. Although the evidence is not completely uniform, there are indirect arguments (renal hemodynamic response to RAS blockade, AT1 receptor expression), however, which would be consistent with increased intrarenal action of angiotensin (ANG) II. There is solid evidence that ACE inhibitors effectively interfere with progression of micro-albuminuria both in IDDM and NIDDM. They also prevent progression of advanced renal failure in IDDM, while there is only preliminary evidence in this respect for NIDDM. ACE inhibitors are superior to conventional antihypertensive agents (with the possible exception of some calcium channel blockers), but such superiority is seen only when the levels of blood pressure are relatively high. In diabetic animals, treatment with ANG II receptor blockers interferes with the development of glomerular lesions. In acute and subacute studies on diabetic patients, ANG II receptor blockers reduced albuminuria (or proteinuria) more than beta-blockers. Head-on comparison of equipotent doses ACE inhibitors and ANG II receptor blockers in non-diabetic patients produced equal reductions in proteinuria. The long-term effects of ANG II receptor blockers on progression of advanced diabetic nephropathy is the object of two large international studies. The results will not be available before the year 2000.
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PMID:Diabetes--renal function--what are the special problems? 983 74

Arterial hypertension, which represents a common problem in patients with renal transplant, contributes to the cardiovascular morbidity and mortality of these patients. The most usual immunosuppressive drugs (cyclosporine and FK-506) collaborate on the development of hypertension. Calcium channel blockers are the most habitually used antihypertensive drugs in this population, although its long-term hemodimamycs effects could be deleterious especially in transplanted patients with chronic graft nephropathy. Losartan, a specific blocker of angiotensin II (AT1) receptors, has demonstrated a potent antihypertensive effect with a good safety and tolerance profile. The glomerular effects of losartan could be useful in transplanted patients. The present open, prospective and multicenter study evaluated the efficacy and safety of losartan in the treatment of hypertension in a group of patients with a renal transplant. Seventy-six patients with systolic blood pressure > or = 140 and/or diastolic blood pressure > or = 90 mm Hg, and/or patients on therapy with one antihypertensive drug and related side effects were included. After inclusion, therapy with losartan 50 mg/24 hr was started, discontinuing the previous antihypertensive therapy and/or therapy which caused the side effects. At four weeks, if blood pressure (BP) was not controlled, hydrochlorothiazide 25 mg or furosemide 40 mg/24 hr was added. At baseline and at weeks 2, 4, 8 and 12, the following parameters were monitored: BP, creatinine, hematocrit, hemoglobin, glucose, ions, uric acid, cholesterol, triglycerides, bilirubin, SGOT, SGPT, GGT, LDH, calcium, phosphate, alkaline phosphatase, proteinuria, and both cyclosporine and FK-506 levels in whole blood. Sixty-seven patients completed the 12-week study period. Mean blood pressure decreased from 113 +/- 10 to 102 +/- 9 mm Hg at the end of the study (P < 0.0001); 38 of the 67 patients (56.7%) who completed the study had a SBP lower than 140 mm Hg and a DBP lower than 90. These blood pressures were obtained in 30 patients on monotherapy with losartan (78.9%). Proteinuria decreased significantly at week 4 and was confirmed at week 12, especially in patients with proteinuria > or = 300 mg/24 hr. Nine patients were withdrawn during the study period for different reasons. Serum creatinine showed a slight, non-clinically significant increase at week 4, remaining stable until the end of the study. Two patients developed a mild normocytic anemia, and three others presented a mild impairment of pre-existent anemia. No interactions with cyclosporine or FK-506 were described. These results indicate that losartan is effective in reducing BP in hypertensive patients with a renal transplant. It has a good tolerance profile and does not interfere with immunosuppressive therapy.
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PMID:Efficacy and safety of losartan in the treatment of hypertension in renal transplant recipients. 983 98

We investigated the effect of angiotensin-converting enzyme inhibition on spontaneous nephrosis in Dahl salt-sensitive (Dahl/S) rats. Dahl/S rats fed on a normal sodium diet spontaneously developed nephrosis and mild hypertension from a young age. In young Dahl/S rats, an angiotensin-converting enzyme inhibitor, imidapril, attenuated the development of proteinuria accompanied by a decrease in blood pressure. Methylprednisolone, a potent therapeutic agent for proteinuria, did not affect the development of nephrosis. An angiotensin AT1 receptor antagonist, losartan, but not a Ca2+ channel blocker, verapamil, inhibited the development of nephrosis while both agents decreased blood pressure to a similar extent as imidapril. In mature Dahl/S rats, imidapril suppressed not only the development of proteinuria but also the glomerular lesions. It is concluded that the development of spontaneous nephrosis in Dahl/S rats is mediated by angiotensin II.
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PMID:Involvement of angiotensin II in development of spontaneous nephrosis in Dahl salt-sensitive rats. 987 73

The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective (proteinuria: CA + T: 29.3+/-12.8 mg/24 h, E + T: 31.3+/-13.0 mg/24 h; GS: CA + T: 10.7+/-4.1%, E + T: 8.3+/-4.6%, P < 0.01) than monotherapy (proteinuria: T: 49.3+/-17.3 mg/24 h, CA: 53.2+/-18.1 mg/24 h, E: 51.1+/-26.6 mg/24 h; GS: T: 10.9+/-4.4%, CA: 23.8+/-4%, E: 14.2+/-5.3%, P < 0.05, with control values of proteinuria: 77.6+/-27.1 mg/24 h and GS: 28+/-2.9%). The number of infiltrating ED-1 (rat macrophage marker) macrophages (T: 161.5+/-51.2 cells/field of view, CA: 203.6+/-102.3, E: 178.6+/-35.3, CA + T: 140.2+/-63.2, E + T:128.2+/-75.6), and CD-5+ (rat T cell marker) T lymphocytes (CA + T: 261.5+/-103.6, E + T: 236+/-94.8) was significantly reduced by the treatment protocols (controls: ED-1: 356+/-100, CD-5: 482.9+/-154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.
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PMID:Coinhibition of immune and renin-angiotensin systems reduces the pace of glomerulosclerosis in the rat remnant kidney. 989 70

In the Prague hypertensive rat (PHR), a strain of genetic hypertension derived from Wistar, administration of various antihypertensive drugs (AHD) during the developmental phase of hypertension (weeks 5-9 of life) prevents the rise of blood pressure. However, only drugs blocking the renin-angiotensin system (RAS, i.e. AT1-antagonist losartan and ACE inhibitor perindopril) have a long-term effect on blood pressure leading to values of systolic blood pressure (SBP) of 174.5+/-14.5 and 169.8+/-15.3 mmHg, respectively, at week 30. At this time, control, untreated PHR have a SBP of 222.0+/-16.6 mmHg (p<0.01 for both groups); age-matched PNR (Prague normotensive rat, bred in parallel with PHR from the same parent pair) exhibit values as low as 123.3+/-11.7 mmHg (p<0.01 from all other values). When losartan was administered to another group of PHR not only at weeks 5-9 but once more at weeks of 15-19 of age, the values of their SBP at week 30 were 156.8+/-12.64 mmHg, i.e., values significantly (p<0.01) different not only from 239.7+/-17.59 mmHg (value of the untreated PHR group) but also from 174.5+/-14.5 mmHg (value of PHR to which losartan was administered only once, at weeks 5-9). Thus, twice repeated administration of losartan in young age almost normalizes blood pressure deep into adult age. Proteinuria, a common finding in adult PHR, is also significantly lower in adult age in both groups receiving at weeks 5-9 drugs blocking RAS; the values at week 30 are 4.0+/-0.26 mg/24 h/rat in the losartan and 3.87+/-0.27 in the perindopril group, in contrast to 12.8+/-1.08 (p<0.01 for both groups) in control PHR. In conclusion, early brief administration (weeks 5-9 of life) of RAS-blocking agents to PHR led to long-term antihypertensive and antiproteinuric effects. These effects were significantly intensified by a second brief administration at weeks 15-19.
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PMID:Long-term effect on blood pressure of early brief treatment by different antihypertensive agents: a study in the prague hypertensive rat. 993 30

Angiotensin (Ang) II type 1 (AT1) receptor antagonists are orally active drugs that specifically block the subtype 1 of Ang receptors. In contrast to AT1 receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors block the actions of Ang II incompletely. Furthermore, the bradykinin-potentiating effects of ACE inhibitors may contribute to the mechanism of action of ACE inhibitors. Data in experimental animals suggest that AT1 receptor antagonists decrease the glomerular filtration rate (GFR) to a lesser degree than ACE inhibitors. The greater effect of ACE inhibitors in decreasing glomerular pressure was attenuated with a bradykinin antagonist. In rat models of renal damage with proteinuria, acute reduction of proteinuria was seen with ACE inhibitors but not with AT1 receptor antagonists, whereas long-term reductions of proteinuria were of similar magnitude with both agents. Renal histology after several months revealed that AT1 receptor antagonists and ACE inhibitors were equally renoprotective in various renal damage models. AT1 receptor antagonists, like ACE inhibitors, exhibit a natriuretic effect equal to moderate doses of a thiazide diuretic. In patients with severe volume depletion, use of AT1 receptor antagonists may lead to acute renal failure. Valsartan was tested in a double-blind trial in patients with moderate to severe renal failure and led to a substantial decrease in diastolic and systolic blood pressure, whereas there was no difference from placebo for changes in GFR. Urine protein increased with placebo and decreased with valsartan. The data indicate that valsartan in renal failure patients is effective in lowering blood pressure while leaving renal excretory function unaltered. Whether there is a renoprotective effect can only be shown in long-term trials, which are under way.
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PMID:Valsartan and the kidney: present and future. 1002 53

The benefit of angiotensin-converting enzyme (ACE) inhibitor (i) therapy in diabetic glomerulosclerosis is thought to be largely the result of attenuation of angiotensin II (AngII) effects on blood pressure, glomerular hemodynamics and hypertrophy, and tissue fibrosis. The present study was undertaken to determine whether the addition of AngII receptor antagonist therapy to ACEi therapy in diabetic nephropathy results in attenuation of AngII effects beyond that achieved by ACEi therapy alone. Seven patients were studied as inpatients on the General Clinical Research Center each for 3 consecutive weeks as follows: week 1, the patients' usual regimen which included daily oral moderate to high dose ACEi therapy; week 2, the patients' usual regimen plus oral losartan (an antagonist (a) of the angiotensin type 1 receptor, AT1) 50 mg (n = 3) or 100 mg (n = 4) daily; week 3, return to the patients' usual regimen. Diet, physical activity, and blood glucose were held as constant as possible during the three weeks of daily testing. We found that plasma renin levels increased significantly during combination therapy and then returned to baseline values with discontinuation of AT1a therapy: mean baseline renin values (week 1) 3.0 ng/ml/min +/- 1.1 SE, mean renin values during combination therapy (week 2) 7.0 ng/ml/min +/- 3.2 (p = 0.0078 by Wilcoxon rank sum test), mean renin values after discontinuation of AT1a therapy (week 3) 3.9 ng/ml/min +/- 2.0 (NS compared to baseline values). In addition, 2 patients developed transient hypotension when losartan therapy was initiated. During this short-term study, 24-hour proteinuria, serum creatinine, serum potassium, and plasma aldosterone were not changed significantly by combination therapy. We conclude that in patients with diabetic nephropathy addition of AT1a therapy to ACEi therapy attenuates AngII effects better than ACEi therapy alone. We suggest that combination therapy for the management of diabetic glomerulosclerosis merits further investigation.
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PMID:Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy. 1008 42

The antiproteinuric effect of angiotensin-converting enzyme inhibitors underscores the importance of a hemodynamic injury and the renin-angiotensin system in the proteinuria of various glomerular diseases. Vascular endothelial growth factor (VEGF), a potent promoter of vascular permeability, is induced in mesangial cells by both mechanical stretch and TGF-beta1. This study investigates the effect of TGF-beta blockade, angiotensin II (AngII), and the interaction between AngII and stretch on human mesangial cell VEGF production. Exposure to AngII (1 microM) induced a significant increase in VEGF mRNA and protein levels (1.5+/-0.1 and 1.7+/-0.3, respectively, fold increase over control, P<0.05). The AngII receptor (AT1) antagonist Losartan (10 microM) prevented AngII-induced, but not stretch-induced, VEGF protein secretion (AngII 1.7+/-0.3, AngII + Losartan 1.0+/-0.1, P<0.05; stretch 2.4+/-0.4, stretch + Losartan 2.6+/-0.5). Stretch-induced VEGF production was also unaffected by the addition of an anti-TGF-beta neutralizing antibody (stretch 2.85+/-0.82 versus stretch + anti-TGF-beta 2.84+/-0.01, fold increase over control). Simultaneous exposure to both AngII and stretch for 12 h had an additive effect on VEGF production (AngII 1.6+/-0.1, stretch 2.6+/-0.27, AngII + stretch 3.1+/-0.35). Conversely, preexposure to stretch magnified AngII-induced VEGF protein secretion (unstretched + AngII 1.3+/-0.0, stretched + AngII 1.9+/-0.1, P<0.01) with a parallel 1.5-fold increase in AT1 receptor levels. AngII and stretch can both independently induce VEGF production; in addition, mechanical stretch upregulates the AT1 receptor, enhancing the cellular response to AngII.
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PMID:Interaction of angiotensin II and mechanical stretch on vascular endothelial growth factor production by human mesangial cells. 1020 56

Angiotensin II antagonists block the actions of angiotensin II by occupying the AT1 receptors. With this blockade there is no bradykinin increase, the angiotensin II synthetized by the cardiac chymase is also blocked, and the AT2 receptor is stimulated (antiproliferative effect). In animal experiments, losartan reverses left ventricular hypertrophy, inhibits myocardial fibrosis and diabetic glomerulosclerosis and significantly protects from vascular cerebral diseases. In humans, the efficacy of the angiotensin II antagonists and that of other antihypertensives is similar and is potentiated by the addition of a thiazide. They are very well tolerated and no important adverse reactions are reported. Losartan decreases insulin resistance, has a very favourable hemodynamic and neurohormonal profile in patients with cardiac insuficiency, reverses proteinuria and has a uricosuric effect. Angiotensin II antagonists are a step forward towards the ideal antihypertensive drugs.
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PMID:[Therapy of arterial hypertension with angiotensin receptor blockers]. 1037 49

Due to its hemodynamic, metabolic and growth promoting effects, angiotensin II (AII) may play an important role in the pathogenesis of diabetic kidney disease. Consequently, decreasing the production or cellular action of AII is a rational target for therapeutic attempts aimed at slowing the progression of diabetic nephropathy. Based on their superior renoprotective performance in recent landmark studies, currently ACE inhibitors are the drugs of choice in diabetic patients with microalbuminuria or overt proteinuria. A new class of antihypertensive medications, the AT1 receptor antagonists may represent an alternative to ACE inhibitors in the treatment of diabetic nephropathy. They provide a more complete blockade of the renal renin-angiotensin system and are generally better tolerated than ACE inhibitors. On the other hand, AT1 receptor antagonists do not increase bradykinin levels, an effect that may contribute to the high level of renoprotection achieved by ACE inhibitors. Although human data are not available at this point, ACE inhibitors and AT1 receptor antagonists have similar beneficial effects on proteinuria, renal hypertrophy and glomerulosclerosis in animal models of diabetic kidney disease. Currently several prospective studies are being conducted to compare the efficacy of ACE inhibitors and AT1 receptor antagonists in the treatment of human diabetic nephropathy.
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PMID:AT1 receptor antagonists: a challenge for ACE inhibitors in diabetic nephropathy. 1039 47


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