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)

Prospective, placebo-controlled clinical trials suggest that estrogen may have adverse effects on the vascular system in women. The goal of this study was to determine if 17beta-estradiol (E2) would have adverse effects on the renovasculature in a rat model of renal injury characterized by low nitric oxide (NO) and high angiotensin II (AngII). We studied female Wistar rats that were sham-operated (sham), ovariectomized (OVX), or ovariectomized and replaced with E2 (OVX/E2). All rats were maintained on a high salt diet and renovascular injury was caused by treating rats with an inhibitor of NO synthase, N(omega)-nitro-L-arginine-methyl-ester (L-NAME), for 14 days, plus AngII on days 11 through 14. L-NAME/AngII treatment, as compared to placebo, caused proteinuria, glomerular injury, and fibrinoid necrosis of renal arterioles in sham-operated rats. Ovariectomy reduced L-NAME/AngII-induced renal damage, whereas E2 treatment increased L-NAME/AngII-induced damage in OVX rats. In rats treated with L-NAME/AngII, levels of AngII type 1 receptor (AT(1)R) protein were higher in the renal cortex of sham and OVX/E2 rats than in OVX rats. AT(1)R protein correlated with renal injury. E2 treatment also increased expression of AT(1)R mRNA. Thus, under conditions of low NO and high AngII, E2 exacerbated renal injury. E2-mediated increases in renal cortical AT(1)R expression may represent a novel mechanism for the adverse renovascular effects of estrogen.
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PMID:Estradiol increases proteinuria and angiotensin II type 1 receptor in kidneys of rats receiving L-NAME and angiotensin II. 1702 6

Vascular aging is characterized by endothelial dysfunction that is primarily attributed to increased superoxide production, the exact source of which remains ambiguous. This study compared the NAD(P)H and xanthine oxidase (XO) systems as sources of superoxide and impaired vascular function in aging. Male Sprague Dawley rats, 4-months-old (young) and 18-months-old (Aging), were used. Systolic blood pressure was higher (36 +/- 3%) in the aging group compared with young rats, and this was accompanied by reduced acetylcholine-induced renal vasodilatation. Urinary excretion of nitrite was lower in the aging rats (P < 0.05), and this was associated with reduced nitric oxide synthase (NOS) activity and reduced eNOS and iNOS protein expression in the aorta. Aged rats showed a n approximately twofold increase in free radical generation, as evident by increased plasma 8-isoprostane level, and an approximately fourfold increase in proteinuria compared with the young rats. Vascular NADP(H) oxidase was unchanged between both groups, as was the expression of p67phox or p47phox components of NAD(P)H oxidase. However, XO activity was increased (19 +/- 1%; P < 0.05) as well as XO expression in the aorta of aging rats. These results suggest that increased free radical generation-associated increase in SBP in aging rats is XO but not NAD(P)H oxidase-dependent.
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PMID:Oxidative stress-associated vascular aging is xanthine oxidase-dependent but not NAD(P)H oxidase-dependent. 1703 Dec 61

Nitric oxide (NO) depletion in rats induces severe endothelial dysfunction within 4 days. Subsequently, hypertension and renal injury develop, which are ameliorated by alpha-tocopherol (VitE) cotreatment. The hypothesis of the present study was that NO synthase (NOS) inhibition induces a renal cortical antioxidative transcriptional response and invokes pro-oxidative and proinflammatory gene expression due to elimination of dampening effects of NO and enhanced oxidative stress. Male Sprague-Dawley rats received NOS inhibitor N(omega)-nitro-l-arginine (l-NNA, 500 mg/l water) for 4 (4d-LNNA), 21 (21d-LNNA), or 21 days with VitE in chow (0.7 g/kg body wt/day). Renal cortical RNA was applied to oligonucleotide rat arrays. In 4d-LNNA, 21d-LNNA, and 21d-LNNA+VitE, 120, 320, and 184 genes were differentially expressed, respectively. Genes related to glutathione and bilirubin synthesis were suppressed during 4d and 21d-LNNA and not corrected by VitE. Proteinuria, tubulointerstitial macrophages, and heme-oxygenase-1 (HO-1) expression were strongly correlated. Remarkably, pro-oxidative genes were not induced. Inflammation- and injury-related genes, including kidney injury molecule-1 and osteopontin, were unchanged at day 4, induced at 21d, and partly corrected by VitE. Superimposing HO-1 inhibition on NOS inhibition had no impact on the development of hypertension. To summarize, renal expression of genes involved in synthesis of the antioxidants glutathione and bilirubin seemed directly NO dependent, but there were no direct effects of NO depletion on pro-oxidant systems. This indicates that renal transcriptional regulation of two defense systems, glutathione and bilirubin syntheses, seems to depend upon adequate NO synthesis. Interaction between NO synthesis and heme degradation pathways for blood pressure regulation was not found.
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PMID:Transcriptome-based identification of pro- and antioxidative gene expression in kidney cortex of nitric oxide-depleted rats. 1704 89

Gestational diabetes (GD, characterized by abnormal D-glucose metabolism), intrauterine growth restriction (IUGR, a disease associated with reduced oxygen delivery (hypoxia) to the foetus), and preeclampsia (PE, a pregnancy complication characterized by high blood pressure, proteinuria and increased vascular resistance), induce foetal endothelial dysfunction with implications in adult life and increase the risk of vascular diseases. Synthesis of nitric oxide (NO) and uptake of L-arginine (the NO synthase (NOS) substrate) and adenosine (a vasoactive endogenous nucleoside) by the umbilical vein endothelium is altered in pregnancies with GD, IUGR or PE. Mechanisms underlying these alterations include differential expression of equilibrative nucleoside transporters (ENTs), cationic amino acid transporters (CATs), and NOS. Modulation of ENTs, CATs, and NOS expression and activity in endothelium involves protein kinase C (PKC), mitogen-activated protein kinases p42 and p44 (p42/44(mapk)), calcium, and phosphatidyl inositol 3 kinase (PI3k), among others. Elevated extracellular D-glucose and hypoxia alter human endothelial function. However, information regarding the transcriptional modulation of ENTs, CATs, and NOS is limited. This review focuses on the effect of transcriptional and post-transcriptional regulatory mechanisms involved in the modulation of ENTs and CATs, and NOS expression and activity, and the consequences for foetal endothelial function in GD, IUGR and PE. The available information will contribute to a better understanding of the cell and molecular basis of the altered vascular endothelial function in these pregnancy diseases and will emphasize the key role of this type of epithelium in placental function and the normal foetal development and growth.
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PMID:Equilibrative nucleoside (ENTs) and cationic amino acid (CATs) transporters: implications in foetal endothelial dysfunction in human pregnancy diseases. 1726 15

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). It was recently reported that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of chronic kidney disease (CKD). ADMA is a strong predictor of the progression of CKD as well. However, a role for the ADMA-DDAH in the pathogenesis of CKD remains to be elucidated. This study investigated the effects of DDAH-elicited ADMA lowering on renal function and pathology in a rat remnant kidney model. Four weeks after five-sixths subtotal nephrectomy (Nx), the rats were given tail-vein injections of recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial beta-galactosidase (Adv-LZ) or orally administered 20 mg/kg per d hydralazine (Hyz), which served as a BP control model. In comparison with Adv-LZ or Hyz administration, Adv-DDAH decreased plasma levels of ADMA and inhibited the deterioration of renal dysfunction. Plasma levels of ADMA were associated with decreased number of peritubular capillaries, increased tubulointerstitial fibrosis, and proteinuria levels in Nx rats. These changes were progressed in Adv-LZ-or Hyz-treated Nx rats, which were ameliorated by DDAH overexpression. In addition, semiquantitative reverse transcriptase-PCR and immunohistochemistry for TGF-beta revealed that Adv-DDAH inhibited upregulation of TGF-beta expression in Nx rats. These data suggest that ADMA may be involved in peritubular capillary loss and tubulointerstitial fibrosis, thereby contributing to the progression of CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of CKD.
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PMID:Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. 1742 45

Previous studies have reported that isohumulones, the bitter compounds in beer, improve insulin resistance and hyperlipidemia in several animal models. In this study, we examined whether isohumulones ameliorate renal injury. Dahl salt-sensitive hypertensive rats were fed a low-salt diet (LS), a high-salt diet (HS) or a high-salt diet containing 0.3% isohumulones (HS+IH) for 4 weeks. Urinary nitrite/nitrate (NOx) excretion was measured at 4 weeks along with blood pressure and urinary protein excretion. Renal injury was evaluated histologically and reactive oxygen species (ROS) and nitric oxide (NO) production in the renal cortex was visualized. Oxidative stress and NO synthase (NOS) expression were evaluated by immunohistochemical staining and Western blot analysis. Mean blood pressure was significantly decreased in the HS+IH group compared with the HS group at 4 weeks (158.1+/-8.7 vs. 177.5+/-3.7 mmHg; p<0.05). Isohumulones prevented the development of proteinuria in the HS+IH group compared with the HS group at 2 weeks (61.7+/-26.8 vs. 117.2+/-9.8 mg/day; p<0.05). Glomerulosclerosis and interstitial fibrosis scores were significantly decreased in the HS+IH group compared with the HS group (0.61+/-0.11 vs. 1.55+/-0.23, 23.7+/-6.8 vs. 36.1+/-3.5%; p<0.05 for both). In the HS group, increased ROS and decreased NO were observed in glomeruli in vivo. Isohumulones reduced the ROS production, leading to the restoration of bioavailable NO. Urinary NOx excretion was significantly increased in the HS+IH group compared with the HS group. Furthermore, renal nitrotyrosine was increased in the HS group compared with the LS group, and this effect was prevented by isohumulones. Renal NOS expression did not differ among the three groups. These results suggest that isohumulones may prevent the progression of renal injury caused by hypertension via an anti-oxidative effect.
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PMID:Isohumulones derived from hops ameliorate renal injury via an anti-oxidative effect in Dahl salt-sensitive rats. 1746 Mar 88

Sodium supplementation given for 1 wk to nonpregnant rats induces changes that are adequate to maintain renal and circulatory homeostasis as well as arterial blood pressure. However, in pregnant rats, proteinuria, fetal growth restriction, and placental oxidative stress are observed. Moreover, the decrease in blood pressure and expansion of circulatory volume, normally associated with pregnancy, are prevented by high-sodium intake. We hypothesized that, in these pregnant rats, a loss of the balance between prooxidation and antioxidation, particularly in kidneys and heart, disturbs the normal course of pregnancy and leads to manifestations such as gestational hypertension. We thus investigated the presence of oxidative/nitrosative stress in heart and kidneys following high-sodium intake in pregnant rats. Markers of this stress [8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)) and nitrotyrosine], producer of nitric oxide [nitric oxide synthases (NOSs)], and antioxidants [superoxide dismutase (SOD) and catalase] were measured. Then, molecules (Na(+)-K(+)-ATPase and aconitase) or process [apoptosis (Bax and Bcl-2), inflammation (monocyte chemoattractant protein-1, connective tissue growth factor, and TNF-alpha)] susceptible to free radicals was determined. In kidneys from pregnant rats on 1.8% NaCl-water, NOSs, apoptotic index, and nitrotyrosine expression were increased, whereas Na(+)-K(+)-ATPase mRNA and activity were decreased. In the left cardiac ventricle of these rats, heightened nitrotyrosine, 8-iso-PGF(2alpha), and catalase activity together with reduced endothelial NOS protein expression and SOD and aconitase activities were observed. These findings suggest that oxidative/nitrosative stress in kidney and left cardiac ventricle destabilizes the normal course of pregnancy and could lead to gestational hypertension.
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PMID:Renal and cardiac oxidative/nitrosative stress in salt-loaded pregnant rat. 1765 67

To investigate whether ANG II type 1 (AT(1)) receptor blockade could protect kidney mitochondria in streptozotocin-induced Type 1 diabetes, we treated 8-wk-old male Sprague-Dawley rats with a single streptozotocin injection (65 mg/kg ip; STZ group), streptozotocin and drinking water containing either losartan (30 mg.kg(-1).day(-1); STZ+Los group) or amlodipine (3 mg.kg(-1).day(-1); STZ+Amlo group), or saline (intraperitoneally) and pure water (control group). Four-month-long losartan or amlodipine treatments started 30 days before streptozotocin injection to improve the antioxidant defenses. The number of renal lesions, plasma glucose and lipid levels, and proteinuria were higher and creatinine clearance was lower in STZ and STZ+Amlo compared with STZ+Los and control groups. Glycemia was higher in STZ+Los compared with control. Blood pressure, basal mitochondrial membrane potential and mitochondrial pyruvate content, and renal oxidized glutathione levels were higher and NADH/cytochrome c oxidoreductase activity was lower in STZ compared with the other groups. In STZ and STZ+Amlo groups, mitochondrial H(2)O(2) production rate was higher and uncoupling protein-2 content, cytochrome c oxidase activity, and renal glutathione level were lower than in STZ+Los and control groups. Mitochondrial nitric oxide synthase activity was higher in STZ+Amlo compared with the other groups. Mitochondrial pyruvate content and H(2)O(2) production rate negatively contributed to electron transfer capacity and positively contributed to renal lesions. Uncoupling protein-2 content negatively contributed to mitochondrial H(2)O(2) production rate and renal lesions. Renal glutathione reduction potential positively contributed to mitochondria electron transfer capacity. In conclusion, AT(1) blockade protects kidney mitochondria and kidney structure in streptozotocin-induced diabetes independently of blood pressure and glycemia.
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PMID:Renal mitochondrial impairment is attenuated by AT1 blockade in experimental Type I diabetes. 1802 45

Preeclampsia is a human syndrome characterized by elevated maternal blood pressure and proteinuria. It is the main cause of maternal morbidity and mortality, and fetal metabolic disturbances in developed and developing countries. Fetal complications in preeclampsia have been related with lower placental blood flow. The placenta lacks of innervation, thus vascular tone regulation depends on endothelial release of vasoactive molecules such as adenosine and nitric oxide (NO). Information about NO synthesis and its action in the feto-placental vasculature in preeclamptic pregnancies is controversial mainly due to the use of different methodological approaches, severity of the disease and cell type that had been analyzed. A high plasma level of adenosine has been reported in umbilical vein from preeclampsia compared with normal pregnancies. Since this nucleoside is mainly involved in the regulation of vascular tone and angiogenesis, perhaps through the modulation of potassium channels, it is suggested that it would be involved in the maintenance of normal feto-placental function. In this review we hypothesize a potential adenosine-mediated, NO-dependent mechanism accounting for the feto-placental reduced blood flow exhibited in preeclampsia. We summarize the potential mechanisms involved in the modulation of inducible NO synthase expression and activity in preeclampsia, emphasizing metabolic alterations in the placenta microvascular endothelial function. The involvement of adenosine, nucleoside membrane transporters and adenosine receptors, nuclear factor kappa B (NF-kappaB), potassium channels and angiogenesis, are also discussed regarding abnormal endothelial function in preeclampsia.
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PMID:A hypothesis for preeclampsia: adenosine and inducible nitric oxide synthase in human placental microvascular endothelium. 1835 14

An inverse relationship exists between kallistatin levels and salt-induced oxidative stress in Dahl-salt sensitive rats. We further investigated the role of kallistatin in inhibiting inflammation and fibrosis through antioxidative stress in Dahl-salt sensitive rats and cultured renal cells. High-salt intake in Dahl-salt sensitive rats induced elevation of thiobarbituric acid reactive substances (an indicator of lipid peroxidation), malondialdehyde levels, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, and superoxide formation, whereas kallistatin gene delivery significantly reduced these oxidative stress parameters. Kallistatin treatment improved renal function and reduced kidney damage as evidenced by diminished proteinuria and serum urea nitrogen levels, glomerular sclerosis, tubular damage, and protein cast formation. Kallistatin significantly decreased interstitial monocyte-macrophage infiltration and the expression of tumor necrosis factor-alpha, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Kallistain also reduced collagen fraction volume and the deposition and expression of collagen types I and III. Renal protection by kallistatin was associated with increased NO levels and endothelial NO synthase expression and decreased p38 mitogen-activated protein kinase, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression. Moreover, kallistatin attenuated tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression via inhibition of reactive oxygen species formation and p38 mitogen-activated protein kinase and nuclear factor-kappaB activation in cultured proximal tubular cells. Kallistatin inhibited fibronectin and collagen expression by suppressing angiotensin II-induced reactive oxygen species generation and transforming growth factor-beta1 expression in cultured mesangial cells. These combined findings reveal that kallistatin is a novel antioxidant, which prevents salt-induced kidney injury, inflammation, and fibrosis by inhibiting reactive oxygen species-induced proinflammatory cytokine and transforming growth factor-beta1 expression.
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PMID:Salutary effect of kallistatin in salt-induced renal injury, inflammation, and fibrosis via antioxidative stress. 1839 Oct 98


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