Oatp and Mrp mRNA expression of liver transporters in spontaneously hypertensive rats

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(Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,Zunyi Medical University,Zunyi Guizhou 563099,China)

基礎(chǔ)醫(yī)學(xué)研究

OatpandMrpmRNAexpressionoflivertransportersinspontaneouslyhypertensiverats

YueYun,WuYuting,FuShu,QianZhiqiang,LiYeli,YangDanli

(Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,Zunyi Medical University,Zunyi Guizhou 563099,China)

ObjectiveTo investigate the effects of spontaneous hypertension on the mRNA expression of organic anion transporting polypeptides (Oatps) and multidrug resistance-associated proteins (Mrps) of hepatic tissue in spontaneously hypertensive rats (SHR).MethodsFourteen weeks old male SHR were the SHR group (SHR,n=10).The same aged male homologous Kyoto rats (WKY) were the WKY group (WKY,n=10).Rats were routine fed for 12 weeks.The mRNA expression of the major uptake transporter Oatp1a1,Oatp1a4,Oatp1a5 and Oatp1b2 as well as the main efflux transporters Mrp1,Mrp2,Mrp3 and Mrp4 were detected by Real time RT-PCR.The weight change of rats in each group were recorded every two weeks.Blood pressure change was detected in rats with Scientific CODA Kent system.ResultsCompared with the WKY group，the blood pressure in SHR group was significantly increased (Plt;0.05).The mRNA expression of Oatp1a1,Oatp1a4,Oatp1a5,Oatp1b2,Mrp2 and Mrp4 were up-regulated (Plt;0.01) and the mRNA expression of Mrp3 was down-regulated (Plt;0.01) in SHR group.However,the mRNA expression of Mrp1 did not changed significantly (Pgt;0.05).Among four Oatps,the mRNA expression of Oatp1b2 was the highest (32.77% or 79.59% of β-actin) in WKY or SHR groups,and Oatp1a5 was the lowest (0.0033% or 0.0092% of β-actin) in WKY or SHR groups.Among four Mrps,the mRNA expression of Mrp2 was the highest (22.46% or 61.04% of β-actin) in WKY or SHR groups.ConclusionThe mRNA expression of Oatp1a1,Oatp1a4,Oatp1a5,Oatp1b2,Mrp2,Mrp3 and Mrp4 in the main liver transporters of rats were significantly affected by hypertension.However,hypertension has no significant effect on the mRNA expression of Mrp1.

Organic anion transporting polypeptides; multidrug resistance-associated protein; spontaneous hypertension rat

Liver transporters mediate drug uptake and efflux,which play an important role in endogenous and exogenous substances,drug transport and drug-drug interactions[1].And its functional inhibition or deletion is an important factor in the interaction between drug metabolism and disease[2].

Organic anion transporting polypeptides (Oatps/OATPs) are an intake transporter,which belongs to the superfamily of solute carriers (SLC)[1,3].There coding genes are collectively referred as SLCO genes[3].It is an important cell membrane intake protein in animals and human,and has great influence on the absorption,distribution and elimination of internal and external substances,especially drugs[1,3].Humans are represented in OATPs,and rodents are represented in Oatps.Multidrug resistance-associated proteins (Mrps) are the major efflux transporters in liver that mediate the efflux of drugs and metabolites in hepatic[1].Multidrug resistance associated protein responsible for the removal of xenobiotics,and the conjugates and products of oxidative are excreted in two ways:(1) hepatic parenchymal sinusoidal cells,such as Mrp1,Mrp3 and Mrp4; (2) microscopic cells,such as Mrp2[1].

Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and then play vital roles in human pathology,physiology,pharmacology and toxicology.Transporters mediate the absorption,distribution,metabolism and excretion of the drug invivoand thereby further influencing the invivoprocess of the drug[1].Drug efficacy,drug interactions,adverse drug reactions,and drug detoxification are closely related to transporters[4].The changes of the transporters are involved in the invivobehaviour of commonly used antihypertensive drugs.Whether the hypertension affects the liver transporters is not clear.For now,there are few reports on this research at home and abroad.And,our team has made some progress in the study of spontaneously hypertensive rats.Because of this background,we expected to explore whether hypertension has effects on liver transporters.So that we observe the change of genes related to hepatic organic anion transporters (Oatp1a1,Oatp1a4,Oatp1a5,Oatp1b2) and multidrug resistance-associated proteins (Mrp1,Mrp2,Mrp3,Mrp4).

1 Materials and Methods

1.1 Animals 14 weeks old male SHR and WKY(260～300 g) were from the SPF-grade.These rats were purchased from Beijing Weitong Lihua Experimental Animal Technology Co.,Ltd.License number is SCXK (Beijing) 2012-0001.

1.2 Experimental protocol 14 weeks old SHR were the SHR group (SHR,n=10).The same aged made were the WKY group (WKY,n=10).These rats were routine fed for 12 weeks.

1.3 Total RNA isolation and real-time RT-PCR analysis Total RNA was isolated from liver tissue of rats by RNAiso Plus (TaKaRa Biotechnology) and then purified of it.Then the mRNA expressions of Oatp1a1,Oatp1a4,Oatp1a5,Oatp1b2,Mrp1,Mrp2,Mrp3 and Mrp4 were detected by Real time RT-PCR.The gene sequences of rat Oatps and Mrps were accessed from GenBank (Table 1).

The composition of the reaction system:SYBR?GREEN PCR Master Mix 7.5 μl,Upstream and downstream primer mixture 0.5 μl,0.1% DEPC water 4.0 μl,The diluted cDNA samples 3.0 μl,The total volume of the reaction was 15 μl.The process of reaction:Stage 1:Pre-degeneration,95 °C 30min.Stage 2:PCR reaction,55 °C 5 sec; 60 °C 45 sec,40 Cycles.Stage 3:Analysis of melting curve,Starting at 55 °C and decreasing by 0.5 °C in every 5 sec,80 Cycles.The relative expressions of genes were calculated by the 2-△△Ctmethod and normalized to the house-keeping gene β-actin.And the relative transcript levels were calculated as percentage of β-actin.

Tab1PrimerpairsusedinRealtimeRT-PCR

GeneGenBankaccessionNo.Forwardprimer(5'-3')Reverseprimer(5'-3')β-actinOatp1a1Oatp1a4NM-031144NM_017111NM_131906AGCCATGTACGTAGCCATCCCCTGTGACAATGCAGCAGTTCCTAGGCATAGGCATTTGGAACCCTCATA-GATGGGCACAGGCTGCAATC-CTGAAACACCATCAACCAAAG-CACAAAGCAGOatp1a5Oatp1b2Mrp1Mrp2Mrp3Mrp4AF041105NM_03165NM_022281.2NM_012833.2NM_080581.1NM_133411.1GCAGGATGATGTGGATGGAAC-TAACAACATGCTTCGTGGGATAGGATTGTGTATGCCCCTCCCAATCTCTTGCGCTCACAGAAGATCCCCATTCATCAACCTGCTTGCACTGTTCTCACCATTGCGCATGTA-AATCGGATTG-CAGGAGCATGGAAGT-GTGCCCTTCTTTGAGGAAG-TAGGGC-CCAAAGGAAACTG-GAATACGCCG-CATTCAGTTTGAT-GCGGGAGTCTTTTTGCT-GTTTCGGT-GAGGG

1.4 Rat weight and blood pressure detection The body weight changes of the rats in each group were recorded every two weeks using an electronic scale (Beijing Sartorius Electronics Co.,Ltd.).Then,the blood pressure change was detected in the rats with Scientific CODA Kent system (Kent Scientific,USA).

1.5 Statistical analysis All data were described using mean±SEM.The software SPSS18.0 was used for statistical analysis.Two independent samples were determined by two-tailed independent samplest-test.WhenPlt;0.05 orPlt;0.01 the difference was considered statistically significant.

2 Results

2.1 Changes of body weight in rats The body weight changes (Fig1) were increased with age in each group,but there was no statistically difference between WKY group and SHR group (Pgt;0.05).

Fig 1 Changes of body weight of rats in each group(±SEM,n=6)

2.2 Changes of blood pressure in rats The blood pressure was increased with age in SHR group (Fig 2).Compared with the WKY group，the blood pressure of SHR group (Fig 2) was significantly raised (Plt;0.05).

#Plt;0.05 vs WKY. Fig 2 Changes of blood pressure of rats in each group(±SEM,n=6)

2.3 Changes of Oatp1a1,Oatp1a4,Oatp1a5 and Oatp1b2 mRNA levels in liver tissues Among four Oatps,the mRNA expression of Oatp1b2 (Fig 3) was the highest (32.77% or 79.59% of β-actin) in WKY or SHR groups,and Oatp1a5 (Fig 3) was the lowest (0.0033% or 0.0092% of β-actin) in WKY or SHR groups.Compared with WKY group,the mRNA levels of Oatp1a1,Oatp1a4,Oatp1a5 and Oatp1b2 (Fig 3,4) were significantly up-regulated (Plt;0.01) in SHR.

##Plt;0.01 vs WKY. Fig 3 Changes of mRNA expression of Oatp1a1,Oatp1a4 ,Oatp1a5 and Oatp1b2 in liver(±SEM,n=4)

##Plt;0.01 vs WKY Fig 4 Changes of mRNA expression of Oatp1a1,Oatp1a4 ,Oatp1a5 and Oatp1b2 in liver(±SEM,n=4)

2.4 Changes of Mrp1,Mrp2,Mrp3 and Mrp4 mRNA levels in liver tissues Among four Mrps,the mRNA expression of Mrp2 (Fig 5) was the highest (22.46% or 61.04% of β-actin) in WKY or SHR groups.Compared with the WKY group,the mRNA expression of Mrp2 and Mrp4 (Fig 5,6) were up-regulated (Plt;0.01) in spontaneously hypertensive rats,and the mRNA expression of Mrp3 (Fig 5,6) was down-regulated (Plt;0.01).However,the mRNA expression of Mrp1 (Fig 5,6) did not changed significantly (Pgt;0.05).

##Plt;0.01 vs WKY. Fig 5 Changes of mRNA expression of Mrp1,Mrp2,Mrp3 and Mrp4 in liver(±SEM,n=4)

##Plt;0.01 vs WKY. Fig 6 Changes of mRNA expression of Mrp1,Mrp2,Mrp3 and Mrp4 in liver(±SEM,n=4)

3 Discussion

The liver is one of the major detoxification organs,which is of vital importance for the transport,metabolism,elimination and redistribution of drugs.The changes of transporters in the liver can significantly affect the treatment of endogenous and exogenous compounds.At present,there are few reports about the changes of liver transporters in spontaneously hypertensive rats at home and abroad,and this research provides a theoretical basis for it.

OATPs/Oatps,mainly the endogenous and exogenous substances,especially have significant effects on absorption,distribution and elimination of drugs[3].In Oatps,Oatp1a1,Oatp1a4 and Oatp1b2 are the main hepatic uptake transporters[5].Oatps are a non-Na+-dependent solute carrier,which mediates the transfer of organic cationic drugs[6].The current research considered that Oatps mainly mediated the transfer of drugs from blood into hepatocytes[7].In the liver,the functions of rat liver Oatp1a1,Oatp1a4,Oatp1a5 and Oatp1b2 are similar to human OATP1A2,OATP1B1 and OATP1B3[1].

Oatp1a1 is mainly distributed in liver and kidney[1].Rat Oatp1a1 is the first cloned member of the OATP/Oatp gene family,which expresses in liver and kidney and has extensive substrate specificity[8].In our study,the mRNA expression of Oatp1a1 was up-regulated in spontaneously hypertensive rats.Oatp1a4 mainly distributes in the retina,brain,lung and liver,and it expresses highly in the liver[9],which is a specific liver uptake transporter.Oatp1a4 can also cause PFOS sulfation[10],and it can be inhibited by amiodarone[6],thus affecting the uptake of digoxin[6].Our study showed that the mRNA expression of Oatp1a4 was raised in spontaneously hypertensive rat livers.Oatp1a5 major distributes in the lung,brain,intestine and liver tissues[11],which is inhibited by a series of Chinese herbs[12].In addition,Oatp1a5 has a wide range of substrate properties in the liver and is closely related to the low substrate of Oatp[13],and plays an important role in the liver[13].In our research,the mRNA expression of Oatp1a5 was increased in spontaneously hypertensive rat livers.Rat Oatp1b2 is homologous with mouse Oatp1b2,human OATP1B1 and OATP1B3,which plays an important role in the liver intake of drugs,poisons and environmental chemicals[7,14],and it is also the transporters of sodium[13-14].Rat Oatp1b2 is an enzyme resistant inducer[9],which plays an important role in the maintenance of endogenous substances.In our study,we found that the mRNA expression of Oatp1b2 was also increased in spontaneously hypertensive rat livers.It is speculated that hypertension could affect the mRNA expressions of the major hepatic uptakes transporters Oatp1a1,Oatp1a4,Oatp1a5 and Oatp1b2,in which the mRNA expressions of Oatp1a1,Oatp1a4,Oatp1a5 and Oatp1b2 were up-regulated in spontaneously hypertensive rats.Among four Oatps,the mRNA expression of Oatp1b2 (Fig 4) was the highest (32.77% of β-actin),and Oatp1a5 (Fig 4) was the lowest (0.0033% of β-actin) in WKY,which is consistent with the literature[9].In our study,it is interesting to find that the mRNA expression of Oatp1b2 (Fig 4) was the highest (79.59% of β-actin) and Oatp1a5 (Fig 4) was the lowest (0.0092% of β-actin) in SHR which is alike to in WKY.

Mrps are the major efflux transporter in the liver that mediate the efflux of drugs and metabolites in the liver[1].

MRP1 has little or no immune reactivity in normal human liver,but the expression of MRP1 is increased in primary biliary cirrhosis,chronic hepatitis C virus infection and compliant cell necrosis[15].The expression of Mrp1 is also increased in many liver diseases[15].However,in our research,the mRNA expression of Mrp1 in spontaneously hypertensive rat livers was not significantly different.Mrp2 exists in the apical cell membrane,which promotes the elimination of many exogenous substances,the translocation of endogenous and exogenous organic detoxification substances through bile[16].The anomaly expression of Mrp2 in liver diseases has been extensively documented,such as cholestasis,hepatitis,fibrosis,cirrhosis,and liver cancer[17].Studies have found that the mRNA expression increased of Mrp2 could enhance the efflux function of liver cells,reduce the accumulation of toxic components in intrahepatic bile,promote the metabolism of bile acids and reduce the damage to the hepatic[18].In our research,the mRNA expression level of Mrp2 in spontaneously hypertensive rat livers was increased.Mrp3 is a basal efflux pump for the transport of bilirubin glucuronide,which together with Mrp2 regulates conjugated hyperbilirubinemia[19].Normal hepatocytes mainly express MRP2,but the expression of MRP3 is very low or even not expressed.However,under certain pathological conditions,the expression of MRP2 was decreased,while the expression of MRP3 was increased dramatically.The opposite expression patterns of MRP2 and MRP3 were often accompanied in the above diseases[20].In our study,the mRNA expression of Mrp3 in spontaneously hypertensive rat livers was decreased,and the mRNA expression of Mrp2 was increased,thereby,it was speculated that the opposite expression changes of Mrp2 and Mrp3 were also associated with the phenomenon of coupling in hypertension.Mrp4 is a general efflux transporter for drugs and poisons[21].In the model of Mrp4 knoct out in rats with cholestasis,the extent of liver damage was found to be significantly more severe than that in the wild-type rat cholestasis SHR[22],indicated that the Mrp4 gene had a protective effect on the liver.In fact,the mRNA expression of Mrp4 was significantly increased in human advanced hepatocellular carcinoma in various etiology (HCV infection,alcoholic liver disease and primary sclerosing cholangitis)[23].Our research showed that the mRNA expression of Mrp4 was increased.It is speculated that the mRNA expressions of Mrp2,Mrp3 and Mrp4 were influenced by hypertension,but it had no effect on the mRNA expression of Mrp1.At the same time,it is interesting to show that the mRNA expression of Mrp2 among four Mrps was the highest in both WKY and SHR in our study,which should be further evaluated.This suggests that Mrp2 play an important role,and hypertension may affect the expression of Mrp2.

As result,the mRNA expressions of liver transporter Oatp1a1,Oatp1a4,Oatp1a5,Oatp1b2,Mrp2 and Mrp4 in spontaneous hypertensive rats were significantly higher than the WKY group,whereas the mRNA expression of Mrp3 was decreased significantly,and the mRNA expression of Mrp1 had no evident change.It gives us some hints for future study,we plan to do more further research for Oatps (Oatp1a4,Oatp1b2) and Mrp2 protein expression.

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[收稿2017-05-07;修回2017-08-12]

(編輯：譚秀榮)

國(guó)家自然科學(xué)基金資助項(xiàng)目(NO ：81241142)。

楊丹莉，女，博士，教授，碩士生導(dǎo)師，研究方向：心血管藥理學(xué)、抗炎免疫藥理學(xué),E-mail:zmuyangdanli@foxmail.com。

自發(fā)性高血壓大鼠肝臟轉(zhuǎn)運(yùn)體Oatp及Mrp mRNA水平的變化

岳 云，吳雨婷，付 舒，錢志強(qiáng)，李葉麗，楊丹莉

(遵義醫(yī)學(xué)院 基礎(chǔ)藥理教育部重點(diǎn)實(shí)驗(yàn)室暨特色民族藥教育部國(guó)際合作聯(lián)合實(shí)驗(yàn)室，貴州 遵義 563099)

目的探討高血壓對(duì)大鼠有機(jī)陰離子轉(zhuǎn)運(yùn)多肽(organic anion transporting polypeptides,OATPs/Oatps)及多藥耐藥相關(guān)蛋白(multidrug resistance-associated protein,Mrps)mRNA水平的影響。方法14周齡的雄性自發(fā)性高血壓大鼠(Spontaneous Hypertension Rat,SHR)為SHR組(SHR,n=10)，同源正常的京都大鼠(Wistar-Kyoto rat,WKY)為WKY組(WKY,n=10)。常規(guī)飼養(yǎng)12周。每?jī)芍苡涗浉鹘M大鼠體重變化、Kent Scientific CODA系統(tǒng)檢測(cè)大鼠血壓變化。Real time RT-PCR檢測(cè)大鼠肝臟組織中的主要攝取性轉(zhuǎn)運(yùn)體Oatp1a1、Oatp1a4、Oatp1a5、Oatp1b2 及主要外排型轉(zhuǎn)運(yùn)體Mrp1、Mrp2、Mrp3、Mrp4 mRNA的水平。結(jié)果與WKY組相比，SHR組大鼠血壓明顯上升(Plt;0.05)，SHR組大鼠肝臟轉(zhuǎn)運(yùn)體Oatp1a1、Oatp1a4、Oatp1a5、Oatp1b2、Mrp2及Mrp4 mRNA的表達(dá)量顯著增高(Plt;0.01)，而Mrp3 mRNA的表達(dá)量顯著降低(Plt;0.01)，Mrp1 mRNA的表達(dá)量無(wú)明顯變化(Pgt;0.05)。4種OATP中，Oatp1b2 mRNA在WKY(32.77% of f'-actin)及SHR(79.59% of f'-actin)中表達(dá)均最高，Oatpla5 mRNA在WKY(0.0033% of f'-actin )及SHR(0.009 2% of f'-actin)中表達(dá)均最低。4種Mrp中Mrp2 mRNA在WKY(22.46% of f'-actin)及SHR(61.04% of f'-actin)中表達(dá)均最高。結(jié)論高血壓對(duì)大鼠肝臟主要攝取性轉(zhuǎn)運(yùn)體Oatp1a1、Oatp1a4、Oatp1a5、Oatp1b2及主要外排型轉(zhuǎn)運(yùn)體Mrp2、Mrp3、Mrp4 mRNA的表達(dá)有影響，而對(duì)Mrp1 mRNA的表達(dá)無(wú)影響。

有機(jī)陰離子轉(zhuǎn)運(yùn)多肽；多藥耐藥相關(guān)蛋白；自發(fā)性高血壓大鼠

R969.1

A

1000-2715(2017)05-0469-06