Unknown,Transcriptomics,Genomics,Proteomics

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Alteration of Gene Expression Profile in Spontaneously Hypertensive Rats Treated with Protein Hydrolysate of Blue Mussel (Mytilus edulis) by DNA Microarray Analysis

ABSTRACT: The aim of this study was to investigate the antihypertensive effect of enzymatic hydrolysis of blue mussel protein (HBMP) in rats. Spontaneously hypertensive rats (SHRs) were orally administration with high- or low-dose of HBMP for 28 days. Major components of the renin-angiotensin (RAS) system in serum of SHRs from different groups were analyzed, and gene expression profiling were performed in the kidney of SHRs, using the Whole Rat Genome Oligonucleotide Microarray. Results indicated although genes involved in RAS system were not significantly altered, those related to blood coagulation system, cytokine and growth factor, and fatty acids metabolism were remarkablely changed. Several genes which were seldom reported to be implicated in pathogenesis of hypertension also showed significant expression alterations after oral administration of HBMP. SHRs were randomly divided into three groups (n=10): control group (rats were orally administered with water, 3mL), low-dose group (rats were orally administered with HBMP, 10 mg/kg/day, 3mL), and high-dose group (rats were orally administered with HBMP, 20 mg/kg/day, 3mL). After orally administered with HBMP for 4 weeks, all rats were killed and the kidneys were dissected. For each group, equivalent amounts of RNA from four individual rats were mixed, and transcribed to Cy3-labeled cRNA using the Agilent Low Input Quick Amp Labeling Kit (Agilent Technologies, Santa Clara, CA, USA). Then, Cy3-labeled cRNA from each group was hybridized to the Whole Rat Genome Oligonucleotide Microarray ver. 3.0 (4X44k, G2519F-028282) (Agilent Technologies), following the manufacturer's hybridization protocol.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Junli Feng

PROVIDER: E-GEOD-73387 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Tienilic acid (TA) was withdrawn from the US market due to numerous cases of liver necrosis. Two major hypotheses currently used to understand the mechanisms of idiosyncratic reactions such as TA-induced hepatotoxicity are the hapten and danger hypotheses. Both human cytochrome (CYP) P450 2C9 and the rat ortholog CYP 2C11 metabolize TA, and it was reported that a reactive metabolite of TA binds almost exclusively to these enzymes, thus acting as a mechanism-based inhibitor. TA-induced liver toxicity is associated with antibodies against CYP 2C9, thus TA appears to act as a hapten. However, if the binding were limited to CYP 2C, it is unlikely that this would lead to significant cell stress. Thus, if TA does not cause cell stress it would suggest that a drug does not have to generate a âdanger signalâ in order to cause an idiosyncratic drug reaction and acting as a hapten is sufficient. In order to test whether TA can cause cell stress, male Sprague Dawley rats were orally dosed with TA, and hepatic gene expression was profiled at 6 and 24 h after drug administration. Results showed that TA induced robust changes in genes involved in oxidative stress (e.g. aldo-keto reductase, glutathione-S-transferase, thioredoxin reductase, epoxide hydrolase), inflammation and cytotoxicity (e.g. IL-1b, interferon regulatory factor 1, macrophage stimulating protein 1, caspase-12), as well as those promoting liver regeneration (e.g. p27Kip1, DUSP6, serine dehydratase, spectrin bII, inhibin bA). These data support the hypothesis that danger signals in the form of cell-stress proteins and the generation of oxidative stress may be involved in initiating the immune response observed in TA-induced toxicity. Other recent data also indicate that the reactive metabolite of TA binds to other proteins in addition to CYP 2C Experiment Overall Design: Rats were orally dosed with TA or control sodium bicarbonate. Eight animals were divided into two groups: Group 1 consisted of two animals that received a single dose of TA, and the two control animals received only sodium bicarbonate. Group 1 was sacrificed 6 h after drug/vehicle administration. Group 2 also comprised of two animals, and they were given two doses of TA (given at t=0 and t=16 h) and sacrificed at 24 h. Control rats in group 2 received two oral doses of sodium bicarbonate. For microarray analysis, six Affymetrix chips were used: Group 1 samples (3 chips) was comprised of pooled RNA from control rats C1 and C2, and an individual chip for each treated animal T1 and T2; Group 2 (3 chips) pooled RNA from control rats C3 and C4, and an individual chip for each treated animal T3 and T4.

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Alteration of Gene Expression Profile in Spontaneously Hypertensive Rats Treated with Protein Hydrolysate of Blue Mussel (Mytilus edulis) by DNA Microarray Analysis

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