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)

We previously reported a new animal model of progressive glomerulonephritis induced by a single intravenous injection of the anti-Thy-1 monoclonal antibody MoAb 1-22-3 into uninephrectomized rats (Clin Exp Immunol 102: 181-185, 1995). We examined the effects of angiotensin II (Ang II) receptor antagonist (candesartan) on the clinical features and morphological lesions of this new model. By 10 weeks after induction of nephritis, untreated rats had developed hypertension, massive proteinuria, renal dysfunction, and severe glomerular injury, while uninephrectomized control rats had not. There was a significant increase in levels of glomerular protein and cortical mRNA for transforming growth factor-beta (TGF-beta) and type I and type III collagens in untreated nephritic rats. Ten week treatments with candesartan and hydralazine significantly reduced blood pressure (BP) to an equal extent. Candesartan, but not hydralazine, prevented proteinuria, normalized renal function, and ameliorated glomerular injury. Candesartan also reduced levels of glomerular protein and cortical mRNA for TGF-beta and type I and type III collagens, while hydralazine did not. These findings suggest that candesartan prevents progression to end-stage renal failure by modulating the effects of Ang II at least in part on the production of TGF-beta and type I and type III collagens, and not merely on systemic BP.
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PMID:Candesartan prevents the progression of mesangioproliferative nephritis in rats. 940 66

A lot of evidence points to the important role of the renin-angiotensin system in the physiopathology of hypertension and the progression of chronic renal failure. In this review, the authors report the data concerning the protective effects of antagonists of angiotensin II AT1 receptors (AT1ra). The AT1 ra have been shown to have beneficial effects in most experimental models of nephropathy in which they have been tested (renal ischaemia, essential or induced hypertension, glomerulonephritis, 5/6 nephrectomy, renal transplantation, induced diabetes, toxic and radiotherapy-induced nephropathy). Clinical trials confirm these beneficial effects. In healthy subjects and hypertensive patients, the AT1 ra have identical effects to those of angiotensin converting enzyme (ACE) inhibitors on renal haemodynamics. In hypertensives, Candesartan and Irbesartan increase renal blood flow and the glomerular filtration rate and decrease the filtration fraction. Two studies have also shown that Candesartan and Irbesartan reduce proteinuria in diabetic patients. Similar results have been reported in essential hypertension with renal failure. These data suggest that AT1 ra have beneficial effects on the progression of experimental kidney disease and on proteinuria in the clinical setting. Of the pharmacological agents available for use in this class, it is essential to propose molecules whose efficacy in antagonising the effects of angiotensin II lasts throughout the 24 hour period. Clinical trials are under way to evaluate the effects of AT1 ra on renal function in man over a long period.
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PMID:[Are the antagonists of angiotensin II AT1 receptors protectors of the kidney?]. 1044 11

Monotherapy frequently does not cause adequate blood pressure (BP) reduction and goal BP is not achieved. This double-blind, randomized, crossover, placebo-controlled study investigated, using a factorial design, the interaction between a dihydropyridine calcium channel blocking drug (felodipine 5 mg) and an angiotensin type I receptor blocking drug (candesartan 16 mg) on the control of BP as assessed by 24-h ambulatory monitoring. A total of 31 elderly patients with systolic hypertension completed all four arms of the study. Candesartan and felodipine lowered mean 24-h BP to a similar extent (candesartan 12.2 +/- 2.6/7.5 +/- 1.8; felodipine 11.9 +/- 2.2/5.7 +/- 1.4 mm Hg). The combination lowered it by 21.0 +/- 2.1/11.2 +/- 1.2 mm Hg, and this fall was significantly greater than with either of the monotherapies (P < .005) and was fully additive with no interactive term. The responder rate with the combination (90%) was greater than with candesartan (61%) or felodipine (55%). Microalbuminuria or proteinuria was present in 12 of 31 patients at randomization despite previous BP control. Candesartan and the combination both reduced urinary albumin excretion. Albumin excretion was not reduced by felodipine despite BP control similar to that achieved with candesartan. Side effects were infrequent and were fewer on the combination than on placebo or on the monotherapies. The combination of felodipine 5 mg and candesartan 16 mg has additive effects on BP in elderly patients with systolic hypertension. The combination was well tolerated and is suitable for use in patients who do not have an adequate response to monotherapy.
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PMID:A comparison of candesartan, felodipine, and their combination in the treatment of elderly patients with systolic hypertension. 1207 57

The authors recently observed an age-dependent reduction in the diuretic and natriuretic responses to plasma volume expansion in uninephrectomized control and glucose-intolerant rats. To determine the involvement of angiotensin II AT receptors in this phenomenon, the authors tested the hypothesis that chronic candesartan treatment preserves renal excretory function in the uninephrectomized rat. Control and glucose-intolerant rats underwent right nephrectomy at 4 weeks of age. Two weeks later, the animals in each group were further subdivided and maintained on tap water containing either candesartan cilexetil (10 mg. kg(-1). day(-1) ) or vehicle. Renal excretory responses to acute extracellular fluid volume expansion (5% of body weight over 30 min) were determined in the 9-month-old conscious animal. Candesartan treatment markedly reduced the mean arterial pressure of controls and glucose-intolerant rats. Nonetheless, the baseline rates of fluid and electrolyte excretion, as well as the saline volume-induced diuretic, natriuretic, and kaliuretic responses, were greater in the candesartan-treated rats than in their vehicle-treated counterparts. The augmented baseline rates of fluid and sodium excretion in candesartan-treated rats were caused by a reduction in tubular reabsorption activity and an increase in glomerular filtration rate. However, the candesartan-mediated enhancement in saline volume-induced diuresis and natriuresis was caused by a reduction in tubular reabsorption activity. In addition to improving renal function, candesartan treatment reduced proteinuria in both groups. In conclusion, chronic blockade of the angiotensin II receptors exerts hypotensive and renoprotective effects in the aging uninephrectomized rat.
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PMID:Renoprotective effects of chronic candesartan treatment in uninephrectomized rat. 1250 25

Candesartan shows beneficial end-organ effects in the kidney. Some of these appear to be related not to the reduction in systemic blood pressure induced by candesartan, but to its blockage of intrarenal angiotensin II type I (AT1) receptors. Initial studies have shown that renal vascular resistance was reduced in patients with hypertension receiving candesartan, and urinary albumin excretion was reduced in patients with type 2 diabetes mellitus and concomitant microalbuminuria or proteinuria. These findings, together with the results of recently published large randomized studies involving diabetic patients with hypertension treated with other angiotensin II receptor blockers, indicate that this class of drugs is beneficial in preventing the development or progression of diabetic nephropathy. This review summarizes the large body of findings related to these renoprotective effects and reported during experimental and clinical research on candesartan for the treatment of diabetic nephropathy.
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PMID:Candesartan: nephroprotective effects and treatment of diabetic nephropathy. 1294 96

Angiotensin II type-1 receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis. Recently, an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy, but the mechanism responsible for the effect has not yet been determined. In this study, we examined additive effect of these two drugs in chronic glomerulonephritis patients. Ten patients with biopsy-proven primary glomerulonephritis (eight IgA nephropathy patients, two membranous nephropathy patients), non-nephrotic proteinuria (protein, 0.5 to 3.5 g/day) received candesartan cilexetil (2 or 4 mg) for 8 weeks. After the 8 weeks, a combination of perindopril erbumine (1 or 2 mg) and candesartan cilexetil was administered to the patients. Perindopril was stopped after the 8-week administration of the two drugs. Candesartan alone reduced proteinuria by 13%. Combination of these two drugs induced a more remarkable reduction of proteinuria (48%; p < 0.05 vs other periods). The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria. The combination of drugs also reduced the amount of urinary type-IV collagen excretion. An additive effect of ACEI and ARB on proteinuria and urinary type-IV collagen excretion was recognized in patients with chronic glomerulonephritis.
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PMID:[Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor in patients with chronic glomerulonephritis]. 1450 19

It has becoming clear that angiotensin receptor blockers (ARBs) show varying levels of angiotensin II type 1 (AT1) receptor blocking activity. Although the duration of activity and the efficacy on blood pressure of ARB are reported to vary, depending on the agents used, it has not been examined whether the effects on proteinuria and urinary nitrite/nitrate (NOx) excretion differ in hypertensive patients with chronic renal disease. In the present study, patients with hypertension (> 140 and/or 90 mmHg) and chronic renal disease (proteinuria > 0.5g/day; serum creatinine < 265 micromol/l or creatinine clearance > 30 ml/min/1.72 m2) were randomly assigned to perindopril- (n = 15), trandolapril- (n = 15), candesartan- (n = 17), and losartan-treated groups (n = 15), and were followed up for 96 weeks. All agents decreased blood pressure to the same level, and none of them had any effect on creatinine clearance. Candesartan, perindopril, and trandolapril reduced proteinuria markedly (from 3.0 +/- 0.6 to 1.8 +/- 0.5 g/day, 2.7 +/- 0.5 to 1.6 +/- 0.4 g/day, and 2.7 +/- 0.5 to 1.7 +/- 0.4 g/day, respectively) at 12 weeks, and the beneficial effect persisted throughout the study. The effect of losartan, however, diminished over the study period. Whereas perindopril, trandolapril, and candesartan markedly increased urinary NOx excretion (from 257 +/- 23 to 1,011 +/- 150 micromol/day, 265 +/- 70 to 986 +/- 130 micromol/day, and 260 +/- 62 to 967 +/- 67 micromol/day at 12 weeks, respectively), a relatively blunted increase was observed with losartan (from 309 +/- 42 to 596 +/- 64 micromol/day). In conclusion, renal action of ARB varies, with relatively less proteinuria-sparing, as well as NOx-enhancing, effects observed with candesartan showing the greatest reduction of proteinuria and greatest enhancement of NOx. Furthermore, renal nitric oxide may contribute to the renal protective action of these agents when administered to patients with chronic renal disease.
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PMID:Differing anti-proteinuric action of candesartan and losartan in chronic renal disease. 1471 78

Hypertension continues to be a major public health issue in the world. To combat this problem, many anti-hypertensive drugs have been developed and proven effective at controlling blood pressure in the last half century. In recent decades, antihypertensive drugs have been shown to have cardiovascular benefits beyond the reduction of blood pressure, and the focus has shifted to clarification of these effects. Angiotensin II receptor antagonists and calcium channel blockers are the most widely used antihypertensive drugs in Japan. However, these two classes of drugs have not yet been compared with respect to their efficacy for treating cardiovascular events. The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial described herein is a prospective, multicenter, randomized, open-label, active-controlled, 2-arm parallel group comparison with a response-dependent dose titration and blinded assessment of endpoints in high-risk hypertensive patients treated with either an angiotensin II receptor antagonist (candesartan cilexetil) or a third-generation calcium channel blocker (amlodipine besilate). The eligibility criteria in this study were 1) age between 20 and 85 years; 2) systolic blood pressure (SBP) > or = 140 mmHg in those below 70 years of age or > or = 160 mmHg in those above 70 years of age or diastolic blood pressure (DBP) > or = 90 mmHg on two consecutive measurements at clinic; and 3) at least one of the following high risk factors for cardiovascular events: a) SBP > or = 2180 mmHg or DBP > or = 110 mmHg on two consecutive visits, b) type 2 diabetes mellitus (fasting blood glucose > or = 126 mg/dl, casual blood glucose > or = 200 mg/dl, HbA1c > or = 6.5%, 2 h blood glucose on 75 g oral glucose tolerance test (OGTT) > or = 200 mg/dl, or current treatment with hypoglycemic therapy), c) history of cerebral hemorrhage, cerebral infarction, or transient ischemic attack until 6 months prior to the screening, d) left ventricular hypertrophy on either echocardiography or ECG, angina pectoris, or history of myocardial infarction until 6 months prior to screening, e) proteinuria or serum creatinine > or = 1.3 mg/dl, and f) symptoms of arteriosclerotic artery obstruction. The therapeutic goals of blood pressure control were set as follows: SBP < 130 mmHg and DBP < 85 mmHg for patients below 60 years of age, SBP < 140 mmHg and DBP < 90 mmHg for those in their 60s, SBP < 150 mmHg and DBP < 90 mmHg for those in their 70s, and SBP < 160 mmHg and DBP < 90 mmHg for those in their 80s. A total of 3,200 patients, equally allocated to each of the two treatment arms, were required based on a two-sided alpha level 0.05 and 90% power. The CASE-J is also the first study to employ the newly developed Automatic Bar Code Data-Capturing/Allocation, Booking & Trial Coding, Data Management (ABCD) system for data collection and management. Enrollment of patients started in September 2001 and ended in December 2002. Follow-up data will be collected every 6 months until December 2005. The CASE-J trial will provide important evidence on the comparative effectiveness of candesartan cilexetil and amlodipine besilate on cardiovascular morbidity and mortality among Japanese. In addition, the use of the ABCD system is expected to contribute to the development of more efficient data management systems for large-scale clinical trials.
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PMID:Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial of cardiovascular events in high-risk hypertensive patients: rationale, design, and methods. 1471 41

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

Angiotensin II (Ang II) and reactive oxidative species (ROS) that are produced by NADPH oxidase have been implicated in the progression of glomerulonephritis (GN). This study examined the effect of simultaneously interrupting Ang II and ROS with an Ang II receptor blocker (ARB), candesartan, and a free radical scavenger, probucol, in a model of progressive mesangioproliferative GN induced by the injection of anti-Thy-1 antibody into uninephrectomized rats. Nephritic rats were divided into four groups and given daily oral doses of the following: Vehicle, 1% probucol diet, 70 mg/L candesartan in drinking water, and probucol plus candesartan. These treatments lasted until day 56. Vehicle-treated nephritic rats developed progressively elevated proteinuria and glomerulosclerosis. Candesartan kept proteinuria significantly lower than vehicle or probucol. The addition of probucol to candesartan normalized urinary protein excretion. Increases in BP in nephritic rats were lowered by these treatments, except with probucol. It is interesting that both glomerular cell number and glomerulosclerosis were significantly decreased by candesartan and normalized by the addition of probucol. Immunohistochemical studies for TGF-beta1, collagen type I, and fibronectin revealed that the combined treatment abolished glomerular fibrotic findings compared with candesartan. In addition, glomerular expression of NADPH oxidase components and superoxide production suggested that the combined treatment completely eliminated NADPH oxidase-associated ROS production. In conclusion, our study provides the first evidence that the antioxidant probucol, when added to an Ang II receptor blockade, fully arrests proteinuria and disease progression in GN. Furthermore, the data suggest that NADPH oxidase-associated ROS production may play a pivotal role in the progression of GN. The combination of probucol and candesartan may represent a novel route of therapy for patients with progressive GN.
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PMID:Addition of the antioxidant probucol to angiotensin II type I receptor antagonist arrests progressive mesangioproliferative glomerulonephritis in the rat. 1646 49


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