UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
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Preeclampsia is a leading cause of maternal and neonatal mortality and morbidity. It is a complex syndrome of undetermined etiologic origin, usually diagnosed during the second half of pregnancy, with clinical features of hypertension, proteinuria, and edema. No cure for preeclampsia exists, except premature delivery. There is increasing evidence that oxidative stress is an important contributing factor to the pathogenesis of preeclampsia. Oxidative stress is defined as an imbalance between reactive oxygen species (ROS), such as nitric oxide (NO*), superoxide anion (O2*-), and hydrogen peroxide (H2O2), and antioxidants, favouring an overabundance of ROS. The consequence of an overproduction of ROS can be observed as increased levels of markers of oxidative stress, such as lipid peroxides. Pregnant women affected by preeclampsia may have abnormal ROS production, particularly NO* and O2*-, abnormal levels of antioxidant defences, and increased placental lipid peroxidation. Several observations suggest that decreased bioavailability of endothelium-derived NO*, due to oxidative destruction of NO* by ROS, might contribute to the impaired endothelium-dependent vasodilatory responses and multisystemic pathology of preeclampsia, a phenomenon in which antioxidant vitamins may play a beneficial role. This review focuses on the rationale for vitamins C and E supplementation toward prevention of preeclampsia, with an emphasis on the limit of our scientific knowledge concerning the deleterious oxidative events taking place in this pathology.
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PMID:Current concepts in the use of antioxidants for the treatment of preeclampsia. 1297 Aug 9

The balance between endothelial nitric oxide (NO) and angiotensin II (Ang II) maintains the homeostasis of the cardiovascular and renal systems. We tested the hypothesis that increased oxidant stress linked to a functional imbalance between NO and Ang II might play a central pathogenetic role in salt-sensitive (SS) hypertension. We studied Dahl SS (DS) rats during the prehypertensive (5 days) and hypertensive (12 weeks) phases of a high-salt (4% NaCl) diet. Control rats received a normal-salt (0.5% NaCl, [NS]) diet. Prehypertensive DS rats (systolic blood pressure [SBP] 138+/-2 mm Hg) manifested a 35% increase (P<0.05) in aortic superoxide (O2-) production without evidence of end-organ damage. Hypertensive DS rats (SBP 214+/-11 mm Hg) had impaired endothelium-dependent relaxation (EDR) and increased aortic O2- production (320%), urinary isoprostane excretion (83%), aortic (20%) and left ventricular (LVH, 21%) hypertrophy, and proteinuria (124%). In prehypertensive DS rats, candesartan (10 mg x kg(-1) x d(-1)) an Ang II type 1 receptor blocker (ARB), normalized O2- production. In hypertensive DS rats, the ARB decreased aortic O2- production by 71% and normalized EDR without affecting SBP (212+/-8 mm Hg), aortic hypertrophy, LVH, or proteinuria. Switching hypertensive DS rats to an NS diet did not affect SBP (208+/-8 mm Hg), LVH, aortic hypertrophy, or proteinuria and had minimal effects on O2- and EDR. Concomitant ARB administration plus a switch to an NS diet normalized SBP (138+/-8 mm Hg) as well as end-organ damage. Dahl salt-resistant rats fed an HS diet for 12 weeks did not show hypertension or increased O2- production. Thus, SS hypertension might represent a specific vascular diathesis linked to functional upregulation of Ang II action (increased O2- synthesis) accompanied by insufficient NO bioavailability, which promotes severe endothelial dysfunction.
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PMID:In salt-sensitive hypertension, increased superoxide production is linked to functional upregulation of angiotensin II. 1297 88

The effect of insulin-resistance syndrome on vascular function has been examined in isolated basilar arteries using the obese Zucker rat (OZR) and age-matched lean littermate controls (lean Zucker rat; LZR) at 36 weeks of age. The OZR showed significantly reduced oral glucose tolerance and increased body weight, blood pressure, proteinuria, plasma levels of triglycerides, cholesterol, and insulin compared with the LZR. The contractile response to serotonin was significantly increased in the OZR. Furthermore, contractions to serotonin in LZR but not OZR were enhanced in the presence of the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (NAME). Relaxations to acetylcholine (ACh), histamine, and A23187 were significantly reduced in precontracted arteries from the OZR. In the presence of NAME, histamine responses were significantly reduced whereas ACh and A23187 responses were almost abolished. Relaxations to free-radical nitric oxide (NO) and papaverine were not different in arteries from the OZR, even though responses to sodium nitroprusside were reduced in the OZR. Western blot and immunofluorescent quantitative analyses of eNOS content in cerebral microvessel fractions and basilar artery preparations, respectively, were not significantly different between OZR and LZR. The results suggest impairment in endothelial function resulting in reduced NO function in the basilar artery from the OZR.
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PMID:Impaired nitric oxide function in the basilar artery of the obese Zucker rat. 1450 35

Wistar Furth (WF) rats do not develop renal injury after severe reduction of renal mass. Because clinical and animal studies suggested that nitric oxide (NO) deficiency occurs and may contribute to chronic renal disease (CRD), the status of the NO system in WF versus Sprague Dawley (SD) rats was examined with the 5/6 renal ablation/infarction (A/I) model of CRD. Eleven weeks after A/I, SD rats developed proteinuria, severe kidney damage, decreased renal function, and marked decreases in total and renal NO synthase (NOS), specifically neuronal NOS. In contrast, WF rats exhibited elevated baseline and maintained post-A/I total NO production, with no decrease in renal cortex NOS activity despite a decrease in remnant neuronal NOS abundance. When low-dose chronic Nomega-nitro-L-arginine methyl ester treatment was added for WF A/I-treated rats, rapid progression of CRD was observed. In conclusion, elevated NO production in WF rats was associated with protection from the progression of CRD after renal mass reduction. The protection might be attributable to greater total and renal NO-generating capacity and increased nephron number, compared with SD rats. NOS inhibition rendered WF rats susceptible to progression, suggesting a possible critical threshold for NO production, below which renal injury occurs.
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PMID:Protection of wistar furth rats from chronic renal disease is associated with maintained renal nitric oxide synthase. 1451 30

Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.
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PMID:Renal effects of omapatrilat and captopril in salt-loaded, nitric oxide-deficient rats. 1456 1

We investigated the renal structural and functional consequences of nitric oxide (NO) deficiency co-treated with angiotensin-converting enzyme inhibitor (ACEi) in 20 adult male Wistar rats and 20 spontaneously hypertensive rats (SHR). The animals were separated into eight groups (n = 5) and treated for 30 days: Control, L-NAME (NO deficient group), Enalapril, L-NAME + Enalapril. The elevated blood pressure in NO deficient rats was partially reduced by enalapril. Serum creatinine was elevated in L-NAME-SHRs and effectively treated with enalapril. The proteinuria was significantly higher only in L-NAME-SHRs, and this was reduced by treatment with ACEi. The glomerular volume density (Vv(gl)) in L-NAME rats, both Wistar and SHR, was greater than in matched control rats, and enalapril treatment effectively prevented this Vv(gl) increase. No significant differences were observed in tubular volume density, Vv(tub), or tubular surface density, Sv(tub), in all Wistar groups. The Vv(tub) was smaller in L-NAME-SHRs than in control SHRs, and this tubular alteration was not prevented by enalapril. The Sv(tub) was not different among the SHR groups. In Wistar rats no changes were seen in vascular surface density, but a greatly increased cortical vascular volume density was seen in the enalapril treated rats. The vascular length density was greatly diminished in NO deficient rats that was effectively prevented with enalapril treatment. The vascular cortical renal stereological indices are normally reduced in SHRs. Administration of enalapril, but not L-NAME, changed this tendency. However, enalapril was not totally effective in preventing vascular damage in SHR NO deficient animals.
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PMID:Kidney adaptation in nitric oxide-deficient Wistar and spontaneously hypertensive rats. 1470 68

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

Male gender is associated with a more rapid progression of renal disease independent of blood pressure, dietary protein intake, or serum lipid levels. Recently, we reported a key role for the intrarenal vasculature in progressive renal disease (Kang D-H, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of endothelium in progressive renal disease. J Am Soc Nephrol 2002, 13:806-816). We hypothesized that estrogen-mediated preservation of the renal vasculature could account for the better renal outcome in female rats. We analyzed micro- and macrovascular changes in the 5/6 remnant kidney (RK) models both in male (n = 24) and female (n = 24) Sprague-Dawley rats up to 12 weeks after renal mass reduction. At 12 weeks, male and female RK rats had equivalent blood pressure, glomerular tuft area, and RK/body weight, but male rats showed worse renal function, proteinuria, glomerulosclerosis (%), and tubulointerstitial fibrosis. At 12 weeks peritubular capillary (PTC) EC proliferation and PTC density were higher in female RK rats whereas macrovascular changes in preglomerular vessels (smooth muscle cell proliferation, medial wall thickening, and adventitial fibrosis) were less prominent. The expression of vascular endothelial growth factor (VEGF) and VEGF type 2 receptor (flk-1) in renal cortex assessed by immunostaining were higher in female RK rats. To dissect the mechanism of sex hormone-induced vascular remodeling and VEGF regulation, we investigated the in vitro effect of 17 beta-estradiol (17 beta E, 10 nmol/L) on proliferation and VEGF expression of renal tubular cells (rat proximal tubular cells), vascular smooth muscle cells (VSMCs), and human umbilical vein endothelial cells (HUVECs). 17 beta E directly stimulated the proliferation of HUVECs, whereas it inhibited serum-induced proliferation of VSMCs. 17 beta E stimulated VEGF mRNA expression both in renal tubular cells and VSMCs. However, when cells were pretreated with a nitric oxide donor to simulate the in vivo condition, 17 beta E inhibited VEGF mRNA expression and protein release in VSMCs. In conclusion, female RK rats developed less glomerulosclerosis and renal failure compared to male RK rats in association with greater preservation of PTC and less preglomerular arteriopathy. Estrogen stimulated basal VEGF expression in renal tubular cells. We propose that estrogen may protect female rats in progressive renal disease by stimulating VEGF expression and maintaining a healthy intrarenal vasculature.
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PMID:The impact of gender on progression of renal disease: potential role of estrogen-mediated vascular endothelial growth factor regulation and vascular protection. 1474 71

A chronic reduction in uterine perfusion pressure in the pregnant rat is associated with significant elevations in mean arterial pressure, proteinuria, and reductions in kidney function as is chronic nitric oxide blockade, suggesting that nitric oxide deficiency may contribute to the clinical manifestations of preeclampsia. The purpose of this study was to determine whether supplementation with L-arginine, the precursor for nitric oxide, attenuates the hypertension produced in response to a chronic reduction in uterine perfusion pressure in the pregnant rat. Reduced uterine perfusion was initiated at day 14 of gestation with arterial pressure determined at day 19 of gestation in conscious, chronically instrumented rats. Arterial pressure was significantly elevated in pregnant rats with chronic reductions in uterine perfusion as compared with pregnant control rats (132+/-2 versus 109+/-2 mm Hg, P<0.01, respectively). Treatment with L-arginine (2%) in the drinking water was initiated at day 10 of gestation. l-arginine supplementation resulted in a significant decrease in arterial pressure in both pregnant rats with reduced uterine perfusion pressure (113+/-2 mm Hg treated, P<0.01 versus untreated pregnant with reduced uterine perfusion pressure) and pregnant control (97+/-3 mm Hg treated, P<0.01 versus untreated pregnant) rats. However, supplementation with L-arginine decreased blood pressure by 19 mm Hg in pregnant with reduced uterine perfusion pressure (untreated versus treated) as compared with 12 mm Hg in pregnant (untreated versus treated) rats. Thus, these results suggest that l-arginine supplementation may be beneficial in attenuating the hypertension in preeclampsia.
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PMID:L-arginine attenuates hypertension in pregnant rats with reduced uterine perfusion pressure. 1521 85

This study was carried out to elucidate whether the protective activity of (-)-epicatechin 3-O-gallate (ECg) against excessive peroxynitrite (ONOO(-)) production, is distinct from the activity of several well-known free radical inhibitors, the ONOO(-) inhibitors ebselen and uric acid, the superoxide anion (O(2)(-)) scavenger copper zinc superoxide dismutase (CuZnSOD) and the selective inducible nitric oxide synthase inhibitor L-N(6)-(1-iminoethyl)lysine hydrochloride (L-NIL). To generate ONOO(-), male Wistar rats (n = 6/group) were subjected to ischaemia-reperfusion process together with lipopolysaccharide (LPS) injection. Although ECg did not scavenge the ONOO(-) precursors nitric oxide (NO) and O(2)(-), it reduced the 3-nitrotyrosine level, a property similar to that of uric acid, but distinct from L-NIL. In addition, the elevation in myeloperoxidase activity was reversed by the administration of ECg, uric acid and SOD, but not by that of L-NIL. Furthermore, ECg was the more potent scavenger of the ONOO(-) decomposition product, the hydroxyl radical (*OH), than any other free radical inhibitor tested. The LPS plus ischaemia-reperfusion process resulted in renal dysfunction, estimated by measuring the parameters of renal function--serum urea nitrogen and creatinine levels. However, administration of ECg ameliorated renal dysfunction more than that of the other free radical inhibitors. Moreover, ECg reduced the excessive uric acid level, while the others did not, suggesting a property of ECg distinct from the others. Furthermore, proteinuria, which was demonstrated by the low- and high-molecular weight (LMW and HMW) protein bands of the sodium dodecyl sulfate-polyacrylamide gel electrophoresis pattern, caused by LPS plus ischaemia-reperfusion, was attenuated by administration of ECg and L-NIL, after which the HMW band intensities decreased and LMW protein bands were absent. This study indicates that, in an in-vivo model of ONOO(-) generation, ECg, L-NIL and uric acid exert stronger protective activity against ONOO(-)-induced oxidative damage than SOD and ebselen, and that the mechanism whereby ECg protects against ONOO(-) is distinct from that of L-NIL or uric acid.
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PMID:(-)-Epicatechin 3-O-gallate ameliorates the damages related to peroxynitrite production by mechanisms distinct from those of other free radical inhibitors. 1500 82

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