UMLS:C0033687 - FACTA Search

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)

VEGF expressed in glomerular podocytes, is known to increase vascular permeability to macromolecules. Angiotensin II can stimulate the release of VEGF, and the protective effects of angiotensin II antagonist against diabetic glomerular injury suggest that the angiotensin II-induced VEGF is an important pathogenetic mechanism in the development of proteinuria during diabetic nephropathy although this mechanism is not fully understood. In this study, the changes of VEGF expression was examined in the experimental diabetic nephropathy to determine whether these changes were modified by renoprotective intervention by blockers of angiotensin II receptors. The streptozotocin- induced diabetic rats were treated with L-158,809, a blocker of angiotensin II receptors, for 12 weeks. Age-matched rats with L-158,809 served as controls. RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of VEGF. A progressive increase in urinary protein excretion was observed in diabetic rats. Glomerular VEGF expression was significantly higher in diabetic rats than in the control groups, with a significant reduction in glomerular VEGF expression and proteinuria in L-158,809- treated diabetic rats. VEGF mRNA was also significantly higher in diabetic kidneys than in the control groups, with a significant reduction in VEGF mRNA in L-158,809-treated diabetic kidneys. These results demonstrates that VEGF expression is significantly increased in diabetic podocytes, and angiotensin II receptor antagonist attenuated these changes in VEGF expression and prevented the development of proteinuria in vivo. Attenuation of increased VEGF expression in podocytes could contribute to the renoprotective effects of angiotensin II receptor antagonists in diabetic nephropathy.
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PMID:Angiotensin II receptor blocker attenuates overexpression of vascular endothelial growth factor in diabetic podocytes. 1503 73

Diabetic nephropathy has become the single most important cause of end-stage renal disease in the USA, Europe and Japan. The earliest marker of incipient diabetic nephropathy is the transition of normoalbuminuria to microalbuminuria at an albumin excretion rate of 20 microg/min. Human studies in patients both with and without diabetic kidney diseases have shown that the severity of baseline proteinuria is an important predictor of the rate of loss of renal function. Moreover, the reduction in protein excretion rate when patients with nephropathies are being treated with antihypertensive agents predicts the efficacy of subsequent renoprotection. Experimental and clinical observations provide the rationale for targeting the renin-angiotensin system as a renoprotective approach in diabetic and nondiabetic proteinuric nephropathies. Losartan (Cozaar, Merck Sharpe and Dohme) is a potent, orally active and highly specific angiotensin-type 1 receptor blocker. In addition to its antihypertensive efficacy, losartan decreases the left ventricular mass index in patients with hypertension, left ventricular end-diastolic and end-systolic volume in subjects with heart failure and prevents cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction. Short-term studies in Type 1 diabetic patients with overt nephropathy have demonstrated that losartan and angiotensin-converting enzyme inhibitors have similar beneficial effects on albumin excretion rate, blood pressure and renal hemodynamics. Losartan also lowered albumin excretion rate in microalbuminuric patients with Type 2 diabetes mellitus. Moreover, the large multicenter Reduction of End points in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial has shown that blockade of angiotensin-type 1 receptor with losartan is superior to conventional antihypertensive therapy in slowing the progression of overt Type 2 diabetic nephropathy. Together, data from clinical trials demonstrate the beneficial effect of angiotensin-type 1 receptor blockers, including losartan, in the primary and secondary prevention of renal disease progression in diabetic patients. Nevertheless, it can be expected that the positive results achieved so far with this class of drugs may be further implemented by including angiotensin-type 1 receptor antagonists as a part of the multidrug approach that may hold more promise for the future of renoprotection in diabetic patients with chronic nephropathy.
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PMID:Losartan in diabetic nephropathy. 1522 8

A characteristic feature of a majority of chronic renal diseases is their progressive course. The speed of deterioration of renal function depends besides an aetiology of a primary disease on the level of systemic (and glomerular) blood pressure and a degree of proteinuria. Angiotensin II plays an important role in the use of hemodynamic and nonhemodynamic factors of progression. Inhibitors of angiotensin converting enzyme or angiotensin antagonists comparable with other hypertensives used in blood pressure control have more substantial renoprotective effects both in diabetic and nondiabetic kidney diseases. A prerequisite of an effective renal protection is reaching the target blood pressure corresponding with present European and American recommended values < or = 130/80 mm Hg. The least risk of chronic renal disease progression is when systolic blood pressure is 110-120 mm Hg and in proteinuria plain 1 g/24 hod. A practical implementation of renal protection is difficult in patients with renal insufficiency in spite of the used combination of angiotensin converting enzyme inhibitors or angiotensin antagonists and other antihypertensives.
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PMID:[Renoprotective effects of antihypertensives]. 1532 61

Losartan is an orally active, selective, nonpeptide, angiotensin-II Type I-receptor antagonist, and was the first drug marketed in this class. It has been approved for the treatment of hypertension, and may be used alone or in combination with other antihypertensive agents. Based on the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, losartan has been approved for the reduction of cardiovascular events in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to black patients. Based on the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, losartan is also indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria, in patients with Type 2 diabetes. The focus of this review is the LIFE study.
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PMID:Losartan for the treatment of hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. 1550 Mar 78

Clinical trials have demonstrated the benefit of blood pressure (BP) reduction in reducing the risk of cardiovascular and renal complications in patients with diabetes mellitus. Incorporation of agents that inhibit the renin-angiotensin-aldosterone system (RAAS) into antihypertensive regimens has been shown to provide reductions in renal and cardiovascular events that are mediated by both BP-dependent and -independent mechanisms. Recent studies exploring these potential mechanisms have demonstrated a direct role of angiotensin II (ATII) in the pathology of the vasculature and other sites of end-organ injury. In animal models of diabetes, inhibition of the RAAS with angiotensin-converting enzyme (ACE) inhibition or angiotensin type 1 (AT(1)) receptor blockade has been shown to prevent atherosclerosis, an effect that was independent of BP reduction. In addition to its direct effects on the vasculature, ATII also has direct detrimental effects on end organs, including the kidney and the heart, which lead to the development of proteinuria and left ventricular hypertrophy (LVH), respectively. Left ventricular hypertrophy has been shown to be predictive of cardiovascular and renal events, and the benefits of RAAS inhibition with angiotensin receptor blocker therapy are accompanied by a reduction in LVH. In addition to preventing the cardiovascular and renal complications of diabetes, the RAAS blockade has also been shown, in several large randomized clinical trials, to inhibit new onset of diabetes. Recent studies have revealed that many tissues, including pancreatic islets and adipose tissue, have a local RAAS. In the diabetic rat model (Zucker diabetic fatty rats), pancreatic islets exhibit an increased intraislet expression of ACE and AT(1) as well as increased intraislet fibrosis, apoptosis, and oxidative stress. The local RAAS also appears to play a role in the function of the adipocyte. Angiotensin II inhibits adipocyte differentiation, potentially decreasing the storage capacity of adipose tissue. The reduced capacity of adipose tissue to store fatty acids may cause their accumulation in other tissues, leading to insulin resistance and development of diabetes. Collectively, these studies demonstrate that ATII has direct effects on multiple tissues, and inhibition of ATII action in these tissues may be responsible for many of the clinical benefits observed with RAAS inhibition.
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PMID:The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications. 1553 6

Renin angiotensin system inhibitor therapy is seldom offered to individuals who have diabetes and advanced chronic kidney disease because of safety concerns. In this post hoc, secondary analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, angiotensin antagonism risk/benefit profile was assessed in 1513 individuals with type 2 diabetes and overt nephropathy. Incidence of ESRD, hospitalizations for heart failure, withdrawals for adverse events, and proteinuria during losartan or conventional treatment were compared within three tertiles of baseline serum creatinine concentration (highest, 2.1 to 3.6 mg/dl; middle, 1.6 to 2.0 mg/dl; lowest, 0.9 to 1.6 mg/dl). Losartan decreased the risk of ESRD by 24.6, 26.3, and 35.3% in highest, middle, and lowest tertiles, respectively. For every 100 patients with serum creatinine >2.0, 1.6 to 2.0, or <1.6 mg/dl, respectively, 4 yr of losartan therapy was estimated to save 18.9, 8.4, and 2.9 ESRD events and US$1,502,855, US$1,021,770, and US$528,591 costs for renal replacement therapy. Losartan also decreased the hospitalizations for heart failure by 50.2 and 45.1, in the highest and middle tertile, respectively. Withdrawals for adverse events other than heart failure were comparable between tertiles and treatment groups. Proteinuria decreased more on losartan than on placebo in all tertiles (highest, 24 versus -8%; middle, 16 versus -8%; lowest, 15 versus -10%). In proteinuric individuals with type 2 diabetes, losartan therapy reduced ESRD and hospitalizations for heart failure and was well tolerated at all levels of renal function. Angiotensin II antagonism is a suitable and well-tolerated treatment for individuals with type 2 diabetes even with GFR levels approaching renal replacement therapy.
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PMID:Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results. 1557 15

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria <2000 mg/g or >/=2000 mg/g, within the higher proteinuria stratum (>/=2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.
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PMID:Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study. 1587 78

Angiotensin II plays a crucial role in pathologic processes of chronic allograft nephropathy (CAN) leading to chronic and progressive renal allograft dysfunction (CRAD). Systemic and glomerular hypertensions together with proteinuria occur in CAN under conditions of JGA hypertrophy with up-regulated RAS activity in the renal allograft, and they represent independent factors of rapid progression of chronic renal allograft failure. ACEi are safe and efficient antihypertensives with renoprotective effects in patients with CAN. Favorable response to ACEi has been reflected in diminished proteinuria, slow increase of creatininemia, regulation of arterial hypertension and better long-term survival of patients and kidney allografts. Our pilot study highlights the importance of ACEi therapy in CAN after renal transplantation from elder donors (>55 years).
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PMID:[The significance of angiotensin converting enzyme inhibitors in therapy in chronic allograft nephropathy]. 1605 83

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 renin-angiotensin-aldosterone system (RAAS) is a well known regulator of blood pressure (BP) and determinant of target-organ damage. It controls fluid and electrolyte balance through coordinated effects on the heart, blood vessels, and Kidneys. Angiotensin II (AII) is the main effector of the RAAS and exerts its vasoconstrictor effect predominantly on the postglomerular arterioles, thereby increasing the glomerular hydraulic pressure and the ultrafiltration of plasma proteins, effects that may contribute to the onset and progression of chronic renal damage. AII may also directly contribute to accelerate renal damage by sustaining cell growth, inflammation, and fibrosis. Interventions that inhibit the activity of the RAAS are renoprotective and may slow or even halt the progression of chronic nephropathies. ACE inhibitors and angiotensin II receptor antagonists can be used in combination to maximize RAAS inhibition and more effectively reduce proteinuria and GFR decline in diabetic and nondiabetic renal disease. Recent evidence suggests that add-on therapy with an aldosterone antagonist may further increase renoprotection, but may also enhance the risk hyperkalemia. Maximized RAAS inhibition, combined with intensified blood pressure control (and metabolic control in diabetics) and amelioration of dyslipidemia in a multimodal approach including lifestyle modifications (Remission Clinic), may achieve remission of proteinuria and renal function stabilization in a substantial proportion of patients with proteinuric renal disease. Ongoing studies will tell whether novel drugs inhibiting the RAAS, such as the renin inhibitors or the vasopeptidase inhibitors, may offer additional benefits to those who do not respond, or only partially respond, to this multimodal regimen.
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PMID:The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease. 1633 78

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