UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the role of aldosterone in mediating cardiovascular damage, we performed ablation/replacement experiments with aldosterone in a rat model of cardiac injury. Administration of angiotensin II and Nomega-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor) to male rats drinking 1% saline caused hypertension, severe biventricular myocardial necrosis, proteinuria, and fibrinoid necrosis of renal and cardiac vessels. Removal of aldosterone by adrenalectomy or through administration of the selective aldosterone antagonist eplerenone markedly reduced the cardiac and renal damage without significantly altering blood pressure. Aldosterone infusion in adrenalectomized, glucocorticoid-replaced L-NAME/angiotensin II-treated animals restored damage. Thus, we identified aldosterone as a critical mediator of L-NAME/angiotensin II induced vascular damage through mechanisms apparently independent of its effects on systolic blood pressure.
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PMID:Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. 1101 44

Nitric oxide (NO) serves many functions within the kidney, and recent evidence suggests that NO contributes to glomerular injury. Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from human pheochromocytoma. Recent studies showed that plasma AM concentrations correlated with the extent of proteinuria. We have examined the possible role of these two agents by studying plasma and urinary total nitrite (NO-2 + NO-3) and AM levels in children with minimal change nephrotic syndrome (MCNS). In comparison with healthy controls, children with MCNS had increased urinary nitrite excretion (micromol/mg urinary creatinine), irrespective of whether the disease was in relapse or remission (3.2+/-0.2 in relapse, n=13; 1.9+/-0.3 in remission, n=12; 1.0+/-0.2 in controls, n=10, P<0.05). Plasma nitrite levels (micromol/l) were high in relapse compared with controls (53.2+/-8.7 vs. 32+/-4.0, P<0.05). Plasma AM levels (pmol/ml) were decreased in relapse (27.6+/-1.4 in relapse, 43.3+/-1.2 in remission, 41.5+/-1.6 in controls, P<0.05). Urinary AM levels (pmol/mg urinary creatinine) were significantly higher in relapse than in remission and in controls (156+/-43 in relapse, 56+/-18 in remission, 36+/-16 in controls, P<0.05). Our data indicate that NO may play a role in mediating the clinical manifestations of MCNS in children. However, changes in AM levels may be the result of heavy proteinuria.
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PMID:Adrenomedullin and nitrite levels in children with minimal change nephrotic syndrome. 1109 16

Chronic nitric oxide (NO) synthase (NOS) inhibition results in renal injury. Hypertension is an important risk factor for renal injury. We studied the influence of preexistent hypertension on the sensitivity for renal injury induced by chronic NOS inhibition in rats. Spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with 3, 10, 30 and 100 mg/l Nomega-nitro-L-arginine (L-NNA) until death. Systolic blood pressure and proteinuria were measured regularly and compared with time-control measurements in untreated SHR and WKY. In WKY, 3 and 10 mg/l L-NNA did not affect systolic blood pressure, while 30 and 100 mg/l L-NNA resulted in an increase in systolic blood pressure after 12 and 4 weeks, respectively. In contrast in SHR, every dose of L-NNA resulted in an increase in systolic blood pressure after 2 weeks. In WKY, 3 and 10 mg/l L-NNA did not affect proteinuria or survival, while 30 and 100 mg/l L-NNA resulted in an increase in proteinuria after 30 and 9 weeks, and a median survival of 36 and 12 weeks, respectively. In SHR, 3, 10, 30 and 100 mg/l L-NNA resulted in an increase in proteinuria after 30, 12, 3 and 3 weeks, and a median survival of 41, 20, 5 and 3 weeks, respectively. Thus, at every dose of the inhibitor, chronic NOS inhibition resulted in far earlier increases in systolic blood pressure and proteinuria and a marked increase in mortality in SHR as compared to WKY. Indeed, a very low dosage of L-NNA that caused no harm in WKY was followed by marked increases in proteinuria and blood pressure and decreased survival in SHR. Hypertension strongly increases the vulnerability to cardiovascular risk factors that compromise the NO-system.
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PMID:Predisposition of spontaneously hypertensive rats to develop renal injury during nitric oxide synthase inhibition. 1113 73

Chronic iron (Fe) overload is associated with a marked increase in renal tissue iron content and injury. It is estimated that 10% of the American population carry the gene for hemochromatosis and 1% actually suffer from iron overload. The mechanism of iron overload-associated renal damage has not been fully elucidated. Iron can accelerate lipid peroxidation leading to organelle membrane dysfunction and subsequent cell injury/death. Iron-catalyzed generation of reactive oxygen species (ROS) is responsible for initiating the peroxidatic reaction. We investigated the possible association of oxidative stress and its impact on nitric oxide (NO) metabolism in iron-overload-associated renal injury. Rats were randomized into Fe-loaded (given 0.5 g elemental iron/kg body weight as iron dextran; i.v.), Fe-depleted (given an iron-free diet for 20 weeks), and control groups. Renal histology, tissue expression of endothelial and inducible nitric oxide synthases (eNOS and iNOS), renal tissue expression of nitrotyrosine, plasma, and renal tissue lipid peroxidation product, malondialdehyde (MDA), and plasma and urinary NO metabolites (NOx) were examined. Iron overload was associated with mild proteinuria, tissue iron deposition together with significant glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Rare focal glomerulosclerosis and tubulointerstitial changes were noted in normal controls. No renal lesions were observed in Fe-depleted rats. Iron deposits were seen in glomeruli, proximal tubules, and interstitium. The iron staining in the distal tubules was negligible. Both plasma and renal tissue MDA and renal tissue nitrotyrosine were increased significantly in Fe-loaded rats compared with control rats. In contrast, Fe-depleted animals showed a marked reduction in plasma and renal tissue MDA and nitrotyrosine together with significant elevation of urinary NOx excretion. In addition, iron-overload was associated with up-regulation of renal eNOS and iNOS expressions when compared with the control and Fe-depleted rats that showed comparable values. In conclusion, chronic iron overload resulted in iron deposition in the glomeruli and proximal tubules with various renal lesions and evidence of increased ROS activity, enhanced ROS-mediated inactivation, and sequestration of NO and compensatory up-regulation of renal eNOS and iNOS expressions. However, iron depletion was associated with reduced MDA and tissue nitrotyrosine abundance, increased urinary NOx excretion, normal nitric oxide synthase (NOS) expression, and absence of renal injury. These findings point to the possible role of ROS in chronic iron overload-induced renal injury.
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PMID:Association of renal injury with increased oxygen free radical activity and altered nitric oxide metabolism in chronic experimental hemosiderosis. 1114 Jul 2

To elucidate the role of nitric oxide (NO) and renin-angiotensin system (RAS) in the development of salt-sensitive hypertension, we investigated the pressor responses and renal histologic changes after long-term inhibition of endogenous NO synthesis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats under salt-re-stricted conditions that exaggerate RAS activation. Male DS and DR rats (6 weeks old) were fed with a low-salt (0.3%) diet for 5 weeks. NG-nitro-L-arginine (L-NA; dissolved in 60 mg/L deionized water), an arginine analogue acting as a NO-inhibitor, was also administered for 5 weeks. L-NA administration induced a gradual increase in systolic blood pressure (SBP) in both strains, and the pressor response in DS rats was apparently more enhanced relative to that in DR rats. Urinary nitrate plus nitrite (u-NOx) excretion was decreased by L-NA, with a significant negative correlation between SBP and u-NOx excretion in DS rats but not in DR rats. Plasma renin activity and urinary aldosterone level were significantly increased in L-NA-treated DS rats on week 5. Marked histologic changes with glomerular sclerosis and increased proteinuria and urinary N-acetyl-beta-glucosaminidase excretion were found in L-NA-treated DS rats but not DR rats. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that angiotensin II type 1 receptor (AT1R) mRNA level was significantly lower in DS rats than in DR rats at week 2, and that L-NA administration significantly reduced glomerular AT1R level of DS rats at week 5, possibly because of downregulation. Our results showed that, even under sodium restriction, the pressor response and renal injury induced by chronic NO inhibition were markedly more enhanced in DS rats than in DR rats, which indicates that depletion of NO participates in both the development of hypertension and glomerular injury in DS rats through a potential activation of RAS irrespective of sodium loading. These data suggest that endogenous NO is an essential determinant of salt-sensitive hypertension in DS rats.
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PMID:The role of nitric oxide and the renin-angiotensin system in salt-restricted Dahl rats. 1128 Dec 41

Overexpression of inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of lupus glomerulonephritis. Mycophenolate mofetil (MMF), a novel immunosuppressive agent, is currently used in organ transplantation and under evaluation for treatment of autoimmune disorders. Mycophenolic acid, the active metabolite of MMF, has been shown to suppress cytokine-induced nitric oxide production in vitro. The aim of this study was to evaluate the effect of MMF on the expression of renal cortical iNOS mRNA and protection against glomerulonephritis in MRL/lpr mice. Three-month-old MRL/lpr mice (n = 6) displaying clinical symptoms of glomerulonephritis were treated for 3 months with MMF (90 mg/kg/day) dissolved in a vehicle. Controls were age- and sex-matched mice (n = 6) that received the vehicle alone. By reverse-transcription competitive polymerase chain reaction, we found that the renal cortical iNOS/beta-actin mRNA ratio was reduced by 30.8% (P <.05) in MMF-treated mice. Furthermore, MMF significantly reduced urinary nitrite production and degree of glomerulosclerosis. The glomerular volume was reduced by 17.5% (P <.001). Proteinuria was also significantly reduced in the MMF-treated group. However, by electrophoretic mobility shift assay, the nuclear binding of nuclear factor-kappaB (NF-kappaB) was not affected by MMF treatment. We conclude that in addition to its immunosuppressive action, MMF may reduce renal cortical iNOS mRNA expression and diminish glomerulosclerosis in MRL/lpr mice independent of modulation of the NF-kappaB pathway.
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PMID:Mycophenolate mofetil reduces renal cortical inducible nitric oxide synthase mRNA expression and diminishes glomerulosclerosis in MRL/lpr mice. 1143 30

We previously demonstrated that a methionine-threonine-supplemented low (8.5%) casein diet (8.5CMT) reduced symptoms such as proteinuria in nephritic rats without severe protein malnutrition. In this study, we examined whether or not L-arginine supplementation to 8.5CMT would exacerbate proteinuria and other symptoms in nephritic rats. Male Wistar rats with glomerulonephritis induced by a single intravenous injection of nephrotoxic serum were fed either a 20% casein diet (control), 8.5% casein diet, 8.5CMT, or L-arginine-supplemented 8.5CMT (8.5CMTA) for 16 days. The 8.5CMTA, as compared with the 8.5CMT, aggravated proteinuria and glomerulonephritis. Administration of L-N(G)-nitroarginine methyl ester, an inhibitor of nitric oxide synthase, to 8.5CMTA-fed nephritic rats by drinking water for 14 days canceled the adverse effect of L-arginine on proteinuria and histopathological damage in glomeruli. These results suggest that the supplementation of L-arginine makes exacerbation via nitric oxide production in glomerulonephritis.
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PMID:Arginine as an exacerbating factor for glomerulonephritis in rats fed a methionine-threonine-supplemented low casein diet. 1144 Jan 31

Nitric oxide (NO) regulates inflammatory responses partly by cell-specific inhibition of the transcription factor nuclear factor kappaB (NF-kappaB). This study investigated the effect of continuous oral administration of an NO donor (molsidomine [Mol]), NO precursor (L-arginine [L-arg]), or selective inhibitors of inducible NO synthase (iNOS; aminoguanidine [AG], L-N(6)-(1-iminoethyl)lysine [L-NIL]) on the progression of tubulointerstitial inflammation and NF-kappaB activation in a non-immune model of chronic glomerular disease (Adriamycin nephropathy [AN]), from day 8 until day 30 after disease induction. On day 30, rats with AN had heavy proteinuria, reduced creatinine clearance, and tubulointerstitial disease. Treatment with both AG and L-NIL exacerbated the progression of AN as evidenced by (1) increased renal cortical malondialdehyde; (2) reduced creatinine clearance; and (3) increased tubular atrophy, interstitial volume, and monocyte infiltration. Unexpectedly, Mol also increased renal malondialdehyde and worsened tubular injury, whereas L-arg had no effect. The increase in renal cortical NF-kappaB activation in AN was not altered by AG, L-NIL, or Mol, but the mRNA expression of monocyte chemoattractant protein-1, interleukin-10, and osteopontin were elevated in these groups. Nitrite release from kidney slices reduced in AN. Treatment with Mol restored renal nitrite release to normal, whereas neither L-arg nor the NOS inhibitors had an effect. It is concluded that endogenous iNOS-derived NO has a protective role against tubulointerstitial injury and cytokine production in AN. However, the pro-oxidant activity of NO donors may limit their potential benefit in proteinuric renal disease.
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PMID:Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats. 1146 42

Anew model of thrombotic microangiopathy (TMA) was previously developed, and it was demonstrated that endothelial nitric oxide (NO) synthase (NOS) is upregulated in glomeruli in this model. It was hypothesized that the synthesis of NO, a potent vasodilator and platelet inhibitory factor, is induced as a defense mechanism. The goal of this study was to clarify the role of NO in this model. Ex vivo experiments using Western blotting and functional assays demonstrated upregulation of endothelial NOS in isolated glomeruli from TMA rats. In in vivo experiments, five groups of rats were studied, including rats with TMA treated with vehicle, N(G)-nitro-L-arginine methyl ester (L-NAME) (a NOS inhibitor), or L-N(6)-(1-iminoethyl)lysine (L-NIL) (a specific inducible NOS inhibitor) and normal control rats treated with vehicle or L-NAME. Blood urea nitrogen levels, BP, urinary nitrate/nitrite excretion, and proteinuria were measured. Histologic assessments using periodic acid-Schiff staining and immunohistologic studies with markers for endothelium, platelets, fibrin, cell proliferation, and apoptosis were also performed. L-NAME inhibition of NO synthesis in rats with TMA resulted in more severe glomerular and tubulointerstitial injury, which was accompanied by thrombus formation and a marked loss of endothelial cells, with more apoptotic cells. These changes were associated with severe renal function deterioration. In contrast, these features were less pronounced in the vehicle- or L-NIL-treated rats with TMA and were absent in the control animals. In conclusion, inhibition of NO production in this model of TMA markedly exacerbated renal injury. The absence of effects with L-NIL treatment suggests a minor role for inducible NOS in this model. These results suggest that production of NO, most likely by endothelial cells, is an important protective mechanism in TMA.
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PMID:Protective role of nitric oxide in a model of thrombotic microangiopathy in rats. 1156 7

Chronic nitric oxide (NO) synthase inhibition in rats causes hypertension, renal vascular injury, and proteinuria. NO deficiency increases superoxide (O(2)(-)) activity, but the effects of antioxidant treatment on renal injury have not been studied in this model. Exposure of rats to N omega-nitro-L-arginine (L-NNA) for 4 d markedly decreased NO-dependent relaxation in aortic rings and increased glomerular and renal interstitial monocyte influx, but renal O(2)(-) activity was not increased. After 7 d, BP and proteinuria were significantly increased. After 21 d of L-NNA treatment, rats displayed severe hypertension, decreased GFR, marked proteinuria, glomerular ischemia, renal vascular and tubulointerstitial injury, and complete loss of NO-dependent relaxation. Renal O(2)(-) activity was markedly increased [lucigenin-enhanced chemiluminescence (LEC), 279 +/- 71 versus 50 +/- 7 counts/10 mg, P < 0.01; electron paramagnetic resonance spectroscopy, 0.57 +/- 0.05 versus 0.34 +/- 0.04 U/10 mg, P < 0.05]. Apocynin, a specific inhibitor of NADPH oxidase, and diphenyleneiodonium, an inhibitor of flavin-containing enzymes, completely inhibited LEC signals in vitro, whereas allopurinol had no effect, indicating that NAD(P)H oxidase plays a major role in superoxide production in the kidney. Endothelial function remained impaired during cotreatment with alpha-tocopherol and there was no effect on hypertension or tubulointerstitial injury, but glomerular ischemia, decreases in GFR, and renal vascular injury were prevented and proteinuria was ameliorated. Renal LEC signals were intermediate between control and L-NNA-alone values (181 +/- 84 counts/10 mg). Chronic NO synthase inhibition in rats results in marked increases in renal cortical O(2)(-) activity, mediated by flavin-dependent oxidases. The absence of early increases in renal O(2)(-) activity, in the presence of endothelial dysfunction and macrophage influx, indicates that increased renal O(2)(-) activity is neither attributable to NO deficiency per se nor solely related to macrophage influx. The improvement of glomerular function and amelioration of renal vasculitis and proteinuria with vitamin E cotreatment indicate that oxidants are involved in the pathogenesis of renal injury in this model. However, markedly impaired endothelial function and unabated hypertension persist with vitamin E treatment and seem to be directly attributable to NO deficiency.
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PMID:Vitamin E alleviates renal injury, but not hypertension, during chronic nitric oxide synthase inhibition in rats. 1172 26

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