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Title: Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats

Abstract

Inflammation can play a key role in Cd-induced dysfunctions. Quercetin is a potent oxygen free radical scavenger and a metal chelator. Our aim was to study the effect of quercetin on Cd-induced kidney damage and metallothionein expression. The study was performed in Wistar rats that were administered during 9 weeks with either cadmium (1.2 mg Cd/kg/day, s.c.), quercetin (50 mg/kg/day, i.p.) or cadmium + quercetin. Renal toxicity was evaluated by measuring blood urea nitrogen concentration and urinary excretion of enzymes marker of tubular damage. Endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) renal expression were assessed by Western blot. Renal expression of metallothionein 1 and 2 (MT-1, MT-2) and eNOS mRNA was assessed by Northern blot. Our data demonstrated that Cd-induced renal toxicity was markedly reduced in rats that also received quercetin. MT-1 and MT-2 mRNA levels in kidney were substantially increased during treatment with Cd, being even higher when the animals received Cd and quercetin. Renal eNOS expression was significantly higher in rats receiving Cd and quercetin than in animals receiving Cd alone or in control rats. In the group that received Cd, COX-2 and iNOS expression was markedly higher than in control rats.more » In the group Cd + quercetin, no changes in COX-2 and iNOS expression were observed compared with the control group. Our results demonstrate that quercetin treatment prevents Cd-induced overexpression of iNOS and COX-2, and increases MT expression. These effects can explain the protection by quercetin of Cd-induced nephrotoxicity.« less

Authors:
 [1];  [1];  [1];  [2];  [1];  [1];  [3]
  1. Instituto Reina Sofia de Investigacion Nefrologica, Departamento de Fisiologia y Farmacologia, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca (Spain)
  2. Departamento de Bioquimica Clinica, Hospital Universitario de Salamanca, Salamanca (Spain)
  3. Instituto Reina Sofia de Investigacion Nefrologica, Departamento de Fisiologia y Farmacologia, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca (Spain). E-mail: jmlnovoa@usal.es
Publication Date:
OSTI Identifier:
20783410
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 210; Journal Issue: 1-2; Other Information: DOI: 10.1016/j.taap.2005.09.006; PII: S0041-008X(05)00561-2; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; BLOOD; CADMIUM; CARBON MONOXIDE; DAMAGE; EXCRETION; INDIUM OXIDES; INFLAMMATION; KIDNEYS; METALLOTHIONEIN; NITRIC OXIDE; QUERCETIN; RATS; TOXICITY; UREA

Citation Formats

Morales, Ana I., Vicente-Sanchez, Cesar, Jerkic, Mirjana, Santiago, Jose M., Sanchez-Gonzalez, Penelope D., Perez-Barriocanal, Fernando, and Lopez-Novoa, Jose M.. Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats. United States: N. p., 2006. Web. doi:10.1016/j.taap.2005.09.006.
Morales, Ana I., Vicente-Sanchez, Cesar, Jerkic, Mirjana, Santiago, Jose M., Sanchez-Gonzalez, Penelope D., Perez-Barriocanal, Fernando, & Lopez-Novoa, Jose M.. Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats. United States. doi:10.1016/j.taap.2005.09.006.
Morales, Ana I., Vicente-Sanchez, Cesar, Jerkic, Mirjana, Santiago, Jose M., Sanchez-Gonzalez, Penelope D., Perez-Barriocanal, Fernando, and Lopez-Novoa, Jose M.. Sun . "Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats". United States. doi:10.1016/j.taap.2005.09.006.
@article{osti_20783410,
title = {Effect of quercetin on metallothionein, nitric oxide synthases and cyclooxygenase-2 expression on experimental chronic cadmium nephrotoxicity in rats},
author = {Morales, Ana I. and Vicente-Sanchez, Cesar and Jerkic, Mirjana and Santiago, Jose M. and Sanchez-Gonzalez, Penelope D. and Perez-Barriocanal, Fernando and Lopez-Novoa, Jose M.},
abstractNote = {Inflammation can play a key role in Cd-induced dysfunctions. Quercetin is a potent oxygen free radical scavenger and a metal chelator. Our aim was to study the effect of quercetin on Cd-induced kidney damage and metallothionein expression. The study was performed in Wistar rats that were administered during 9 weeks with either cadmium (1.2 mg Cd/kg/day, s.c.), quercetin (50 mg/kg/day, i.p.) or cadmium + quercetin. Renal toxicity was evaluated by measuring blood urea nitrogen concentration and urinary excretion of enzymes marker of tubular damage. Endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) renal expression were assessed by Western blot. Renal expression of metallothionein 1 and 2 (MT-1, MT-2) and eNOS mRNA was assessed by Northern blot. Our data demonstrated that Cd-induced renal toxicity was markedly reduced in rats that also received quercetin. MT-1 and MT-2 mRNA levels in kidney were substantially increased during treatment with Cd, being even higher when the animals received Cd and quercetin. Renal eNOS expression was significantly higher in rats receiving Cd and quercetin than in animals receiving Cd alone or in control rats. In the group that received Cd, COX-2 and iNOS expression was markedly higher than in control rats. In the group Cd + quercetin, no changes in COX-2 and iNOS expression were observed compared with the control group. Our results demonstrate that quercetin treatment prevents Cd-induced overexpression of iNOS and COX-2, and increases MT expression. These effects can explain the protection by quercetin of Cd-induced nephrotoxicity.},
doi = {10.1016/j.taap.2005.09.006},
journal = {Toxicology and Applied Pharmacology},
number = 1-2,
volume = 210,
place = {United States},
year = {Sun Jan 15 00:00:00 EST 2006},
month = {Sun Jan 15 00:00:00 EST 2006}
}
  • Purpose: To investigate the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in cervical cancer and their association with clinical outcome in patients treated with radical radiotherapy. Methods and Materials: One hundred sixty-seven consecutive patients with FIGO Stages IB-IVA squamous cell cervical cancer underwent radical radiotherapy, including external-beam radiotherapy or high-dose-rate brachytherapy, or both, between 1989 and 2002. Immunohistochemical studies of their formalin-fixed, paraffin-embedded tissues were performed. Univariate and multivariate analyses were performed to identify and evaluate the effects of the factors affecting patient survival. Results: Positive immunostainings of iNOS and COX-2 were observed in 58.7% and 64.1%more » of the participants, respectively. The expression of both iNOS and COX-2 was positively correlated (Spearman correlation coefficient = 0.49, p < 0.01), and their overexpression provided independent predictors of distant metastasis (odds ratio = 5.22 and 10.07, respectively; p < 0.01 for all). iNOS- and COX-2-expressing patients had significantly shorter disease-free survival (p < 0.01, both) and cause-specific overall survival (p = 0.01, p < 0.01, respectively). Patients with iNOS-positive/COX-2-positive tumors had the poorest survival rates. Coexpression of iNOS/COX-2, together with bulky tumor and advanced stage were independent prognostic factors for disease-free survival. Conclusion: Overexpression of iNOS or COX-2 or both was associated with decreased survival and a greater propensity to metastasize in cervical cancer patients treated with radiotherapy. Coexpression of iNOS and COX-2 may represent a useful biologic marker in patients receiving radical radiotherapy for cervical cancer.« less
  • There is a need to identify specific biological indicator(s) of cadmium exposure so that the renal damage can be prevented. Towards this end, the usefulness of urinary metallothionein as an indicator of cadmium body burden has been examined. It is found that, in both animals and humans, urinary metallothionein level is related to the hepatic and renal cadmium burdens. Significant correlations are also found between the urinary metallothionein and urinary cadmium and ..beta../sub 2/-microglobulin. Furthermore, it is noted that cadmium-exposed individuals with renal dysfunction excrete significantly more metallothionein than those with normal renal function. Thus it appears that there ismore » merit to include metallothionein among the clinical parameters monitored in cadmium-exposed individuals. More tests are needed to define a critical concentration of metallothionein in urine which is related to the onset of renal dysfunction.« less
  • This report describes the metallothionein (MT) levels and accumulation of mercury, lead, and cadmium, as well as their interaction with tissue zinc, copper, and iron, and the histopathological changes in kidneys of ducks exposed to methylmercury chloride (MeHgCl), lead acetate (PbAc), and cadmium chloride (CdCl{sub 2}), singly or in combination for 13 wk. Forty-eight female Pekin ducks, divided into 8 groups of 6 birds each, were fed diets containing no added metals (control), 8 mg MeHgCl/kg feed, 80 mg PbAc/kg feed, 80 mg CdCl{sub 2}/kg feed, 8 mg MeHgCl + 80 mg PbAc/kg feed, 8 mg MeHgCl + 80 mgmore » CdCL{sub 2}/kg feed, 80 mg PbAc + 80 mg CdCl{sub 2}/kg feed, and 8 mg MeHgCl + 80 mg PbAc/kg feed + 80 mg CdCl{sub 2}/kg feed. Cadmium (Cd) when administered alone or in combination caused a 60-fold increase in kidney MT levels, while methyl-mercury (MeHg) or lead (Pb) administration caused a threefold increase in kidney MT levels. No significant changes in kidney MT levels were observed when metals were administered concurrently when compared with single-treatment groups. Residue analysis revealed accumulation of administered metals in kidney tissue. However, lead administration resulted in accumulation of small amounts of this element in kidney tissue. Simultaneous administration of MeHgCl and PbAc significantly increased the accumulation of lead in kidney when compared with PbAc-treated group. Cadmium when administered alone or in combination caused an increase in the levels of zinc and copper in kidney. Administration of MeHgCl or PbAc either alone or in combination caused increased iron levels in kidney, while cadmium administration either alone or in combination caused decreased iron levels. Administration of cadmium either alone or in combination caused degenerative changes in kidney proximal tubules.« less
  • In this study, the authors have examined the basal level expression and tissue-specific expression patterns of metallothionein (MT) in Arctic char following metal and E2 (17{beta}-estradiol) treatment. To study the gene regulation in Arctic char, the two MT isoforms were isolated from a lambda-ZAP hepatic cDNA library and characterized. Determination of basal MT and mRNA and MT expression for 10 different tissues revealed a lack of correlation between MT and mRNA and MT levels. The inducibility of MT mRNA and the correlation to resulting MT levels were then determined for liver and kidney. They found a more rapid and strongermore » induction of MT mRNA in liver than in kidney at day 1 and 3 postinjection, whereas the MT protein quantification showed higher MT levels in kidney than in liver at days 3 and 7 postinjection. These discrepancies indicate that differences in metal handling or posttranscriptional regulation of MT exists between tissues. Whereas metals induce MT synthesis, E2 inhibit the hepatic MT expression. To examine the tissue specificity of this inhibition, the authors determined the effect of 17{beta}-estradiol (E2) and two estrogenic PCBs (4{prime}-OH-PCB 30 and PCB 104) on Cd-mediated MT induction in liver and kidney. Although E2 and the estrogenic PCBs inhibited cadmium-mediated hepatic MT induction, these compounds did not interfere with renal MT induction.« less
  • The authors describe here the derivation, characterization, and use of clonal cadmium-resistance (Cd/sup r) strains of the Chinese hamster cell line CHO which differ in their metallothionein (MT) induction capacity. By nondenaturing polyacrylaminde gel electrophoresis, the authors showed that the stable Cd/sup r/ phenotype is correlated with the augmented expression of both isometallothioneins (MTI and MTII). In cells resistant to concentrations of CdCl2 exceeding 20 M, coordinate amplifications of genes encoding both isometallothioneins was demonstrated by using cDNA MT-coding sequence probes and probes specific for 3'-noncoding regions of Chinese hamster MTI and MTII genes. Molecular and in situ hybridization analysesmore » supported close linkage of Chinese hamster MTI and MTII genes, which the authors have mapped previously to Chinese hamster chromosome 3. This suggests the existence of a functionally related MT gene cluster in this species. Amplified Cd/sup r/ variants expressing abundant MT and their corresponding Cd/sup s/ parental CHO cells should be useful for future studies directed toward elucidating the mechanisms that regulate expressions of the isometallothioneins. 59 references, 8 figures.« less