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)

The kidney vasculature is under tonic control by nitric oxide (NO) and in cortex, NO controls RA and Kf. Systemic NO inhibition leads to systemic hypertension, increases in RE, mediated by Ang II and ET, and direct effects on RA and Kf. The relationship between NO and other vasoconstrictor systems is variable. In the conscious relaxed animal, vasoconstrictor activity is low, yet acute NO inhibition leads to pressor and renal vasoconstrictor responses. At physiologic levels, ET unexpectedly is a renal vasodilator, possibly via NO generation at RA. When vasoconstrictor activity is high, NO is very important in maintenance of renal perfusion. Chronic L-NAME produces dose dependent systemic and glomerular capillary hypertension and eventual proteinuria and glomerular damage. NO deficiency is key in this process, although the hypertension becomes refractory to L-arginine administration and dependent on Ang II and the SNS, by mechanisms not yet defined. In contrast, the renal vasculature remains fully responsive to L-arginine, suggesting that pressor and renal vascular responses to chronic NO inhibition are separately regulated. NO generated from iNOS does not normally control BP or renal hemodynamics. The relative contributions of NO from bNOS and eNOS, and importance of NOS in different locations in the kidney, remain to be determined.
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PMID:Importance of nitric oxide in the control of renal hemodynamics. 874 86

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

The glomerulus is a unique vascular network with the potential to express several isoforms of nitric oxide synthase (NOS). Induction of inducible NOS (iNOS) occurs as part of a rapid initial response to immune injury in glomerulonephritis (GN). Studies on rodent models suggest that this is due to activation of transcription factors by reactive oxygen species (ROS), generated in responses to Fcgamma and CR engagement. iNOS operates in a complex milieu among multiple other inflammatory mediators, changing expression of constitutive NOS (endothelial NOS, eNOS), a critical regulator of glomerular function, and auto-regulating its own expression. As yet there is no consensus as to the role of high output NO generated by iNOS in the glomerulus, although many studies have demonstrated that NO inhibition can alter the level of proteinuria and leukocyte infiltration, and other manifestations of injury such as thrombosis, proliferation, and matrix production. This article reviews the evidence accumulated from experimental studies over the past decade, and discusses how these conflicting data can be reconciled to form a working hypothesis on the role of NO in GN.
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PMID:Nitric oxide and glomerulonephritis. 1184 31

In an earlier study, we found increased NO production and NO synthase (NOS) expression in renal and vascular tissues of prehypertensive and adult spontaneously hypertensive rats (SHR). This study was designed to determine the effects of aging and AT-1 receptor blockade (losartan 30 mg/kg/day beginning at 8 weeks of age) on NO system in this model. Compared to the Wistar Kyoto (WKY) control rats, untreated SHR showed severe hypertension, elevated urinary NO metabolite (NO(chi)) excretion, marked upregulations of renal and vascular eNOS and iNOS proteins, normal renal function and heart weight at 9 weeks of age. Hypertension control with either AT-1 receptor or calcium channel blockade (felodipine 5 mg/kg/day) mitigated upregulation of NOS isoforms in the young SHR. With advanced age (63 weeks), the untreated SHR showed increased proteinuria, renal insufficiency, cardiomegaly, reduced urinary NO(chi) excretion and depressed renal and vascular NOS protein expressions as compared to the corresponding WKY group. AT-1 receptor blockade prevented proteinuria, renal insufficiency, cardiomegaly, and renal and vascular NOS deficiency. Thus, in young SHR, hypertension results in compensatory upregulation of renal and vascular NOS, which can be attenuated by vigorous antihypertensive therapy. With advanced age, untreated SHR exhibit cardiomegaly, renal dysfunction and marked reductions of eNOS and iNOS compared with the aged WKY rats. Hypertension control with AT-1 receptor blockade initiated early in the course of the disease prevents target organ damage and preserves renal and vascular NOS.
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PMID:Effects of aging and AT-1 receptor blockade on NO synthase expression and renal function in SHR. 1237 78

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with puromycin aminonucleoside (PAN)-induced NS, rats with protein overload proteinuria, Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked proteinuria, hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS protein abundance in the kidney. Similar results were found in rats with protein overload proteinuria in which proteinuria was present without hypoalbuminemia. In contrast, despite extreme hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS protein abundance in the kidney. Administration of aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound hypoalbuminemia without proteinuria, and in rats with protein overload proteinuria, which had proteinuria without hypoalbuminemia, point to proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.
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PMID:Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria. 1285 18

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

The Wistar-Furth (WF) rat is protected against chronic renal disease (CRD) following 5/6th ablation/infarction vs. the Sprague-Dawley (SD) rat, and protection was associated with preserved renal nitric oxide (NO) production. This study examined CRD induced with repeated administration of puromycin aminonucleoside (PAN). SD PAN developed nephrotic range proteinuria (>1 g/24 h), and at 15 wk severe renal injury developed and the glomerular filtration rate (GFR) was reduced to approximately 10% of sham. Total NO production, renal NO synthase (NOS) activity, and renal neuronal (n) and medullary endothelial (e)NOS abundance were reduced in the SD PAN. WF PAN exhibited less severe initial proteinuria (>400 mg/24 h), which abated within weeks, whereas GFR was normal and injury was minimal at 15 wk. Total NO production and renal NOS activity and abundance were significantly elevated compared with SD PAN. NOS mRNA (nNOS, eNOS, and inducible NOS) was not altered in WF, whereas SD showed significant increases in NOS gene expression with PAN. In conclusion, WF showed resistance to a second model of CRD with maintained renal NOS activity compared with SD.
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PMID:Protection against puromycin aminonucleoside-induced chronic renal disease in the Wistar-Furth rat. 1503 44

Statins, inhibitors of cholesterol biosynthesis, are endowed with pleiotropic effects that may contribute to their favorable clinical results. Hypertensive Dahl salt-sensitive (DS) rats have endothelial dysfunction and cardiorenal injury associated with decreased NO bioavailability and increased superoxide (O2-) production linked to a functional upregulation of angiotensin II. We investigated whether atorvastatin (30 mg/kg per day; by gavage) would prevent endothelial nitric oxide (eNOS) downregulation and the increase in O2- in DS rats, thereby reducing end-organ injury. DS rats given a high-salt diet (4% NaCl) for 10 weeks developed hypertension (systolic blood pressure [SBP] 200+/-8 versus 150+/-2 mm Hg in DS rats fed 0.5% NaCl diet [NS]; P<0.05), impaired endothelium-dependent relaxation, functional upregulation of endothelin-1, left ventricular hypertrophy (LVH; 30%), and proteinuria (167%), accompanied by downregulation of aortic eNOS activity (0.7+/-0.2 versus 1.8+/-0.3 nmol/min per gram protein in NS; P<0.05) and increased aortic O2- (2632+/-316 versus 1176+/-112 counts/min per milligram in NS; P<0.05) and plasma 8-F2alpha isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5+/-0.3 nmol/min per gram protein) as well as the increase in O2- (1192+/-243 counts/min per milligram) and plasma 8-F2alpha isoprostanes, reduced LVH and proteinuria, and normalized endothelial function and vascular response to endothelin-1, although reduction in SBP was modest (174+/-8 mm Hg). Atorvastatin combined with removal of high salt normalized aortic eNOS activity, SBP, LVH, and proteinuria. These findings strongly suggest that concomitant prevention of vascular eNOS downregulation and inhibition of oxidative stress may contribute to the protection against end-organ injury afforded by this statin in salt-sensitive hypertension.
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PMID:Atorvastatin prevents end-organ injury in salt-sensitive hypertension: role of eNOS and oxidant stress. 1523 70

Diabetic nephropathy is the leading cause of end-stage renal disease in the Western hemisphere. Endothelial dysfunction is the central pathophysiologic denominator for all cardiovascular complications of diabetes including nephropathy. Abnormalities of nitric oxide (NO) production modulate renal structure and function in diabetes but, despite the vast literature, major gaps exist in our understanding in this field because the published studies mostly are confusing and contradictory. In this review, we attempt to review the existing literature, discuss the controversies, and reach some general conclusions as to the role of NO production in the diabetic kidney. The complex metabolic milieu in diabetes triggers several pathophysiologic mechanisms that simultaneously stimulate and suppress NO production. The net effect on renal NO production depends on the mechanisms that prevail in a given stage of the disease. Based on the current evidence, it is reasonable to conclude that early nephropathy in diabetes is associated with increased intrarenal NO production mediated primarily by constitutively released NO (endothelial nitric oxide synthase [eNOS] and neuronal nitric oxide synthase [nNOS]). The enhanced NO production may contribute to hyperfiltration and microalbuminuria that characterizes early diabetic nephropathy. On the other hand, a majority of the studies indicate that advanced nephropathy leading to severe proteinuria, declining renal function, and hypertension is associated with a state of progressive NO deficiency. Several factors including hyperglycemia, advanced glycosylation end products, increased oxidant stress, as well as activation of protein kinase C and transforming growth factor (TGF)-beta contribute to decreased NO production and/or availability. These effects are mediated through multiple mechanisms such as glucose quenching, and inhibition and/or posttranslational modification of NOS activity of both endothelial and inducible isoforms. Finally, genetic polymorphisms of the NOS enzyme also may play a role in the NO abnormalities that contribute to the development and progression of diabetic nephropathy.
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PMID:Role of nitric oxide in diabetic nephropathy. 1525 73

In view of the ongoing controversy of cardiorenal safety of selective COX-2 inhibitors (coxibs), the present study was designed to examine the effects of 2 different coxibs, celecoxib and rofecoxib, compared with a traditional NSAID, diclofenac, and placebo on renal morphology and function in salt-sensitive hypertension. Salt-sensitive (DS) and salt-resistant (DR) Dahl rats were fed with NaCl-enriched diet (4% NaCl) for 8 weeks. Diclofenac (DS-diclofenac), rofecoxib (DS-rofecoxib), celecoxib (DS-celecoxib), or placebo was added to chow from weeks 6 to 8. Immunostaining for monocytes/macrophages (ED1) and cytotoxic T lymphocytes (CD8) was performed. In addition, renal morphology and proteinuria were assessed. Renal cortex mRNA was isolated for determination of COX-2, eNOS, and CRP mRNA by real-time reverse-transcriptase polymerase chain reaction. Untreated hypertensive animals showed glomerular injury including collapsing glomerulopathy, mesangial sclerosis, mesangiolysis, extracapillary proliferation, protein drops, and an especially high grade of glomerulosclerosis (P<0.05 versus DR-placebo) and CD8-positive and ED1-positive cells (P<0.01 versus DR-placebo), which was improved by celecoxib but not by diclofenac and rofecoxib. C-reactive protein mRNA in renal cortex was increased in DS-placebo animals (P<0.05 versus DR-placebo) and normalized by celecoxib (P<0.05 versus DS-placebo), whereas eNOS mRNA was decreased in the DS-rofecoxib group (P<0.05 versus DR-placebo, DS-celecoxib, and DS-diclofenac). Proteinuria was observed in hypertensive animals (P<0.0001 versus DR-placebo), increased by rofecoxib (P<0.05 versus DS-placebo), and normalized by celecoxib (P=0.0015 versus DS-placebo). This head-to-head comparison of selective and nonselective COX inhibitors demonstrates differential effects of coxibs on renal morphology and function in salt-dependent hypertension.
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PMID:Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension. 1562 40


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