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microRNAs用于急性肾损伤诊治的研究进展

2015-01-29 孙海棚 孙丽君 梅长林 中华急诊医学杂志

急性肾损伤(AKI)是一种病死率较高的临床综合征,主要有肾前性、药物性和感染中毒性肾损伤等几种类型。尽管对AKI巳经进行了几十年的研究,但现在仍缺乏一种有效的早期诊断及治疗方法。microRNAs(miRNAs)是一种长度为19-25个核苷酸的非编码RNA。 最近几年研究发现miRNAs不仅参与哺乳动物正常组织的生理活动,更能在多种疾病的病理生理过程中发挥重要的调节作用,如肿瘤、心脏疾病和神

急性肾损伤(AKI)是一种病死率较高的临床综合征,主要有肾前性、药物性和感染中毒性肾损伤等几种类型。尽管对AKI巳经进行了几十年的研究,但现在仍缺乏一种有效的早期诊断及治疗方法。microRNAs(miRNAs)是一种长度为19-25个核苷酸的非编码RNA。

最近几年研究发现miRNAs不仅参与哺乳动物正常组织的生理活动,更能在多种疾病的病理生理过程中发挥重要的调节作用,如肿瘤、心脏疾病和神经系统疾病等。miRNAs有望成为AKI领域诊断和治疗的新方法。

1 miRNAs及其作用机制

自2000年C.elegans发现了第一个miRNAlet-7以来,越来越多的miRNAs被发现。一条具有功能的成熟的miRNA形成需要经历3个阶段:首先miRNA基因转录形成一条单链形式的pri-miRNA,pri-miRNA通常包含了成熟miRNA的所有序列;之后pri-miRNA经过进一步剪切和折叠成形成一种具有发卡结构的70个碱基左右的pre-miRNA;pre-miRNA再从胞核进人胞浆,被胞浆中的Dicer酶进一步剪切后形成19-22个碱基的成熟tniRNA。

miRNAs以微泡或与特异蛋白结合的形式存在于循环血中,并且能在室温24h和反复冻融8次情况下保持稳定。

根据miRase数据库,目前所发现人的miRNAs巳超过1000个,可能调控着近60%的人类基因的表达,每个miRNA可以有多个靶基因,几个miRNAs也可调节同一靶基因。

miRNAs通过作用于mRNA间接达到调控靶基因表达的作用。成熟的miRNA可以与Argonaute蛋白家族结合形成一种能与mRNA进行互补配对的复合体(RISC),RISC能抑制靶mRNA的翻译。此外miRNAs还可以直接诱导mRNA降解。因此miRNAs对靶基因主要发挥负性调控作用。

2 miRNAs与AKI

肾小管细胞凋亡是AKI的主要发病机制之一,而miRNAs在细胞凋亡过程中发挥关键的调控作用,在病理情况下部分miRNAs可通过改变其表达量达到促进或延缓组织损伤和细胞凋亡的作用。

如miR-15a和miR-16-l能够封闭凋亡相关的Bcl2基因的表达,miR-34可通过影响P53基因的表达进而发挥抑制细胞凋亡的作用。

在肾脏病领域,生物芯片技术的应用可以很容易分析出肾脏组织特异表达的miRNAs的表达谱,而值得注意的是这些miRNAs的表达量在肾移植后会发生改变Harvey等和Shi等研究发现,特异敲除小鼠肾脏足细胞的Dicer酶基因后会导致小鼠肾脏肾小球硬化、蛋白尿和慢性肾衰竭的发生。这表明miRNAs在肾脏的病理生理过程中发挥重要的调节作用。

Wei等在肾小管细胞Dicer酶基因敲除小鼠模型中发现缺血再灌注对肾脏的损伤作用明显被削弱。Xu等发现经过肾脏缺血预处理(夹闭肾动脉15min)后的小鼠肾脏对再灌注损伤的抵抗力增强。

同时还发现缺血预处理组小鼠肾脏miR-21的表达量明显高于未处理组,而使用特定的核酸抑制剂(LNA)封闭miR-21后,缺血预处理组小鼠的肾脏对缺血再灌注损伤的抵抗力显著降低。

Zhu等的研究也发现封闭人近端肾小管上皮细胞(HK-2)内的miR-181a后,HK-2细胞对药物中毒性AKI的抵抗力增强。这3项研究均表明miRNAs在AKI的发病过程中发挥很关键的调控作用。

3 miRNAs与AKI的诊断

大量研究表明miRNAs在疾病期间及其疾病的不同阶段会出现表达量的变化,并且具有器官组织的表达特异性,因此miRNAs具备作为疾病诊断标志物的特点。

当前miRNAs作为疾病诊断标志物的研究在肿瘤学领域比较多。近几年随着对miRNAs研究的进一步深人,这方面研究已经迅速拓展至非肿瘤学领域。

在急性疾病领域,miRNAs作为早期诊断标志物的研究当前巳有报道,如miR-1、133a、499、208与急性心梗的早期诊断,miR-122与急性肝损伤的早期诊断等。而miRNAs与AKI的早期诊断研究目前尚处于起步阶段。

3.1 组织中miRNAs表达量变化与AKI的诊断

当前有关miRNAs表达量变化与AKI病程进展的关系在组织中研究比较多。Bhatt等发现使用40umol/L的顺铀处理小鼠近端小管细胞后,miR-34a的表达量在4h时出现较明显的上升,并且在之后的8h内始终处于上升状态。

而在使用30mg/kg的顺钼对小鼠进行腹腔注射后发现肾组织中miRNA-34a的表达量在第3天出现明显上升。Wei等夹闭小鼠双侧肾动脉32min后,运用生物芯片分析松夹后12h和48h的肾组织发现,miR-132、362、379表达量出现持续变化。其中miR-132和miR-362的表达量上升,而miR-379的表达量下降。

Godwin等对C57BL/6小鼠夹闭单侧肾动脉30min,使用生物芯片和real-timePCR检测发现肾组织中有9种miRNAs的表达量改变比较明显,其中miR-21和miR-20a在松夹后当天即出现明显的上升;miR-146a、199a-3p、214在3d后才开始上升,其中miR-146a和miR-199a-3p在观察时间内始终处于上升状态,而miR-214则在第21天开始下降;miR-192、-187、805、194在松夹后的当天出现迅速的下降。

Saikumar等对2种AKI动物模型肾组织中miR-21、155、18a的表达量进行了检测。发现在缺血再灌注模型中这3种miRNAs在肾脏皮髓质中均出现明显变化,其中皮质中miR-155在松夹24h出现表达高峰,之后开始下降;而髓质中miR-21和miR-155的表达高峰出现在120h;其余组均在24h出现上升、之后的时间点表达水平基本不变。

在庆大霉素诱导的AKI模型中发现miR-21和miR-155表达量均明显上升,且变化程度与用药剂量无关;miR-18a表达量未发生明显变化。

近几年国内在miRNAs用于AKI诊断的研究也取得了一定的进展。南昌大学第一附属院泌尿外科进行的3项研究均发现,缺血再灌注性AKI小鼠模型肾脏组织中miR-210表达量在松夹后4h出现上升,并在24h左右达到表达高峰。其中刘芬等的研究还发现miR-92a在松夹后4h即出现表达高峰。

3.2 循环血和尿液中miRNAs表达量变化与AKI的诊断

虽然肾脏组织中miRNAs表达量变化与AKI进程直接相关,但检测技术复杂,创伤和风险较大,难以大规模应用于临床。而循环血和尿液较易获得,便于检测和临床应用。并且miRNAs在循环血和尿液中性质稳定,血浆和血清中的含量差异不大,也不易被血透清除。

当前巳报道了几项循环血或尿液中的miRNAs与AKI关系的研究,为循环血和尿液中miRNAs作为生物标志物用于AKI的早期诊断提供了工作基础。

Saikumar等进一步研究发现缺血再灌注大鼠模型循环血中这3种miRNAs均出现明显的下降。而尿液中miR-21上升,miR-155含量未发生变化。

药物性模型组大鼠循环血中3种miRNAs的变化也与药物剂量无关,miR-21表达量下降,miR-155a和miR-18a无明显变化。

尿液中miR-21和miR-155均降低了2倍,也与庆大霉素剂量无关。在之后小规模的临床试验中发现AKI患者尿液中miR-21和miR-155均出现轻度上升。

miR-18a不能在尿液中检测到。南京医科大学的一项研究显示,M7BL/6小鼠的药物性和缺血再灌注性AKI模型尿液中miR-lOa和miR-30d的表达量发生较显著的上升。

Lan等发现AKI小鼠模型的尿液中miR494的表达量早于肌酐出现上升;并且AKI的患者尿液中miR494的表达量比正常人高出约60倍。

汉诺威医学院Lorenzen等对77名AKI患者血浆中的miRNAs进行了一项为期4周的随访研究发现,相对于对照组AKI组患者血浆中有13种miRNAs发生了变化,其中变化较明显的有miR-210、320、16,其中miR-210表达量上升,其余2种miRNAs表达量降低。

阜外医院进行过一项临床研究,使用real-timePCR检测经历心脏体外循环术的120例患者术后第1日早晨单个时间点的血浆和尿液中的miR-21,发现miR-21表达量的上升程度与术后发生AKI的严重程度呈正相关性,甚至可以对患者是否需要行CRRT治疗进行预测,显示其具有诊断AKI的潜质。

西班牙马德里拉蒙和卡哈尔大学医院生物医学研究基金会,对50例肾移植术后的患者血清和尿液中的miR-127、210、126、101检测发现,与健康对照组相比,发生AKI的患者术后血清中miR-127的表达量出现下降,而尿液中的表达量则上升,并且在术后当天即出现表达高峰;血清miR-126的表达量也呈现上升趋势,在移植术后第1天出现表达高峰;血清和尿液中miR-210术后也呈上升趋势,其中血清中的表达高峰在手术当天即出现;而miR-101在血清中的表达高峰也出现在手术当天。这项研究表明这4种miRNAs对AKI具有指示作用,此研究已经在我国申请发明专利。

以上几项研究均表明,无论组织还是体液中miRNAs均随AKI的病程进展而出现表达量的改变,并且部分miRNAs会在AKI早期阶段出现变化,提示miRNAs用于AKI早期诊断的可行性,其中miR-21、210、127、101有望成为AKI的早期诊断标志物。

这些研究也有很多局限性,如早期时间点设置过少、临床试验较少、检测的miRNAs数量少等。所以目前需要一项较系统的研究加以证实。

4 miRNAs与AKI的治疗

疾病发生期间生物细胞内的部分miRNAs的表达量会发生变化。若向细胞内转染某种发生变化的外源性miRNAs或LNA则可能发挥缓解某种疾病的作用。当前使用miRNAs治疗疾病巳有研究,特别在肿瘤学领域,如神经胶质瘤等。而在AKI方面的研究较少。

研究发现内质网性和氧化性应激反应是AKI期间肾小管细胞损伤的主要形式。Muratsu-Ikeda等进行的一项研究发现miR-205在HK-2细胞内质网性和氧化性应激反应的条件下均会发生显著的表达量变化。

向细胞内转染抗-miR-205LNA降低miR-205的含量后发现HK-2细胞对这2种应激的抵抗力明显降低。向细胞内转染外源性的miR-205后HK-2细胞对应激反应的抵抗力则明显增强,细胞的生存率明显提高。而单纯的升高或降低细胞内的miR-205则不会对细胞造成损伤,只是降低miR-205会影响细胞的增殖。

目前的一些研究表明间质干细胞内皮祖细胞对AKI具有一定的治疗作用。微泡是细胞间传递信息的一种介质,富含mRNA和miRNAS。

Gatti等将间质干细胞中分离出的微泡注射到AKI大鼠模型后,发现大鼠对AKI的抵抗力增强,肾小管细胞的再生也明显加快。而使用RNA酶钝化微泡中的RNA后,这种保护效应显著降低。

Cantaluppi等也进行了一项类似的研究,向模型体内注射从内皮祖细胞分离出的微泡也能增强大鼠对AKI的抵抗力。

之后他们使用RNA酶处理微泡和向内皮祖细胞中转染Dicer酶及转染抗-miR-l26LNA和抗-miR-2%LNA封闭微泡中含量较高的miR-126和miR-296后,模型鼠的肾功能明显下降,微泡的保护作用也消失。

上述几项研究无论是在细胞水平还是动物水平,改变miRNAs的表达量对AKI均具有一定的缓解作用。而Zhou等的研究发现降低神经胶质瘤小鼠模型体内miR-21的含量能抑制肿瘤的生长,其机制为miR-21含量的降低能激活调亡相关的caspase9和caspase3蛋白的表达,进而促进肿瘤细胞调亡。

而caspase9和caspase3蛋白是AKI期间诱导肾小管细胞凋亡的主要蛋白。而Xu等的实验降低缺血预处理组小鼠体内的miR-21的表达量后,肾脏损伤加重。

而在使用氯化钴处理而制造的人肾小管上皮细胞缺氧模型中,增加miR-21的量,能够显著抑制缺氧相关的factor-a的表达量。

这几项实验提示升高miR-21表达量可能会减轻AKI期间肾小管细胞的凋亡,对AKI发挥一定的治疗作用。此外Aguado-Fraile还发现miR-127能通过作用于KIF3B而达到对缺血再灌注性大鼠肾小管上皮细胞的保护作用

5 问题与展望

依靠miRNAs对疾病进行早期诊断和治疗具有重大的临床意义,但同时也存在很多问题。如诊断方面检测费用高、数据的重复性差。

此外,AKI本身就是机体一系列病理状态的一种,循环血中miRNAs表达量的变化可能受到其他器官疾病的影响,其特异性尚需进一步研究证实。

而尿液中的miRNAs直接来源于肾脏,受其他器官疾病的影响较少,特异性更高,但尿液中miRNAs的水平容易受尿液浓缩程度及AKI期间少尿甚至无尿的影响,不利于检测的进行。

并且循环血和尿液中miRNAs的含量均较低,对检测的灵敏度有很高的要求。因此,寻找一种灵敏度高、操作简便且成本低廉的检测方法是目前循环血和尿液miRNAs作为诊断标志物亟待解决的问题。

此外,仅使用一种miRNAs往往诊断率不高,若将多种miRNAs组合使用并联合其他AKI早期诊断标志物,制成一种试剂盒形式,可有望显著提高AKI早期诊断的准确性。

在治疗方面,外源性合成的miRNAs和LNA价格昂贵,且缺乏临床试验,治疗效果和药物的安全性问题尚需进一步证实。

此外,全身性的改变某种miRNA的表达量在治疗AKI的同时,是否会对机体的其他组织器官产生影响也需研究证实。miRNAs作为新兴的诊断标志物在未来的疾病诊断和治疗中会有很好的应用前景。

在肾脏病领域,通过对miRNAs广泛而深入的研究,有望使其从实验走向临床。发现可被用于AKI诊断或治疗的miRNAs也将会是转化医学的一项重大突破。

中华急诊医学杂志 2014年5月第23卷第5期

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createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2005410, encodeId=2c9a200541028, content=<a href='/topic/show?id=d09f155461e' target=_blank style='color:#2F92EE;'>#RNAs#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15546, encryptionId=d09f155461e, topicName=RNAs)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=05a2499, createdName=dzx0922889, createdTime=Tue Mar 10 02:45:00 CST 2015, time=2015-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=14953, encodeId=7e241495339, content=AKI is bad to person !, beContent=null, objectType=article, channel=null, level=null, likeNumber=168, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1aae1611537, 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encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
  2. 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createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2005410, encodeId=2c9a200541028, content=<a href='/topic/show?id=d09f155461e' target=_blank style='color:#2F92EE;'>#RNAs#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15546, encryptionId=d09f155461e, topicName=RNAs)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=05a2499, createdName=dzx0922889, createdTime=Tue Mar 10 02:45:00 CST 2015, time=2015-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=14953, encodeId=7e241495339, content=AKI is bad to person !, beContent=null, objectType=article, channel=null, level=null, likeNumber=168, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1aae1611537, createdName=loveios, createdTime=Mon Feb 02 15:37:00 CST 2015, time=2015-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380469, encodeId=4b341380469d8, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f13d475, createdName=mashirong, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396898, encodeId=dfd51396898d4, content=<a href='/topic/show?id=8bee565436d' target=_blank style='color:#2F92EE;'>#损伤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=56543, encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
    2015-11-27 xjy02
  3. 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encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
    2015-11-01 angle宋琪

    管用 感觉对实验很有帮助 分析的很到位

    0

  4. 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createdName=loveios, createdTime=Mon Feb 02 15:37:00 CST 2015, time=2015-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380469, encodeId=4b341380469d8, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f13d475, createdName=mashirong, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396898, encodeId=dfd51396898d4, content=<a href='/topic/show?id=8bee565436d' target=_blank style='color:#2F92EE;'>#损伤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=56543, encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
    2015-07-29 sundong

    如何少引起对别的器官的反应呢

    0

  5. 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createdName=loveios, createdTime=Mon Feb 02 15:37:00 CST 2015, time=2015-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380469, encodeId=4b341380469d8, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f13d475, createdName=mashirong, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396898, encodeId=dfd51396898d4, content=<a href='/topic/show?id=8bee565436d' target=_blank style='color:#2F92EE;'>#损伤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=56543, encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
    2015-04-11 x35042875

    轻度肾脏疾病对母亲和婴儿可能会增加孕期风险

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=1857342, encodeId=3830185e3426e, content=<a href='/topic/show?id=3f48525849' target=_blank style='color:#2F92EE;'>#CRO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5258, encryptionId=3f48525849, topicName=CRO)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c30265, createdName=jiafufeng@yaho, createdTime=Thu Jan 07 04:45:00 CST 2016, time=2016-01-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2084117, encodeId=7433208411ef4, content=<a href='/topic/show?id=61f411e013b' target=_blank style='color:#2F92EE;'>#Micro#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11701, encryptionId=61f411e013b, topicName=Micro)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, 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createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2005410, encodeId=2c9a200541028, content=<a href='/topic/show?id=d09f155461e' target=_blank style='color:#2F92EE;'>#RNAs#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15546, encryptionId=d09f155461e, topicName=RNAs)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=05a2499, createdName=dzx0922889, createdTime=Tue Mar 10 02:45:00 CST 2015, time=2015-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=14953, encodeId=7e241495339, content=AKI is bad to person !, beContent=null, objectType=article, channel=null, level=null, likeNumber=168, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1aae1611537, createdName=loveios, createdTime=Mon Feb 02 15:37:00 CST 2015, time=2015-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380469, encodeId=4b341380469d8, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f13d475, createdName=mashirong, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396898, encodeId=dfd51396898d4, content=<a href='/topic/show?id=8bee565436d' target=_blank style='color:#2F92EE;'>#损伤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=56543, encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
    2015-04-11 x35042875

    轻度肾脏疾病对母亲和婴儿可能会增加孕期风险

    0

  7. [GetPortalCommentsPageByObjectIdResponse(id=1857342, encodeId=3830185e3426e, content=<a href='/topic/show?id=3f48525849' target=_blank style='color:#2F92EE;'>#CRO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5258, encryptionId=3f48525849, topicName=CRO)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c30265, createdName=jiafufeng@yaho, createdTime=Thu Jan 07 04:45:00 CST 2016, time=2016-01-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2084117, encodeId=7433208411ef4, content=<a href='/topic/show?id=61f411e013b' target=_blank style='color:#2F92EE;'>#Micro#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11701, encryptionId=61f411e013b, topicName=Micro)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Fri Nov 27 06:45:00 CST 2015, time=2015-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=42126, encodeId=246f421264f, content=管用 感觉对实验很有帮助 分析的很到位, beContent=null, objectType=article, channel=null, level=null, likeNumber=177, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0eb81660032, createdName=angle宋琪, createdTime=Sun Nov 01 12:03:00 CST 2015, time=2015-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=33753, encodeId=459733e5378, content=如何少引起对别的器官的反应呢, beContent=null, objectType=article, channel=null, level=null, likeNumber=185, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3ykRSkuxjt93yc9tvDWfIQItrwiaKSCps5kyrTyDlwic2FgoCWe88wR3ZiaggKYGueDIp26zVgnbzriaQ/0, createdBy=89d71602869, createdName=sundong, 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createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2005410, encodeId=2c9a200541028, content=<a href='/topic/show?id=d09f155461e' target=_blank style='color:#2F92EE;'>#RNAs#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15546, encryptionId=d09f155461e, topicName=RNAs)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=05a2499, createdName=dzx0922889, createdTime=Tue Mar 10 02:45:00 CST 2015, time=2015-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=14953, encodeId=7e241495339, content=AKI is bad to person !, beContent=null, objectType=article, channel=null, level=null, likeNumber=168, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1aae1611537, createdName=loveios, createdTime=Mon Feb 02 15:37:00 CST 2015, time=2015-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380469, encodeId=4b341380469d8, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f13d475, createdName=mashirong, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396898, encodeId=dfd51396898d4, content=<a href='/topic/show?id=8bee565436d' target=_blank style='color:#2F92EE;'>#损伤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=56543, encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
    2015-03-10 dzx0922889
  8. [GetPortalCommentsPageByObjectIdResponse(id=1857342, encodeId=3830185e3426e, content=<a href='/topic/show?id=3f48525849' target=_blank style='color:#2F92EE;'>#CRO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5258, encryptionId=3f48525849, topicName=CRO)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c30265, createdName=jiafufeng@yaho, createdTime=Thu Jan 07 04:45:00 CST 2016, time=2016-01-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2084117, encodeId=7433208411ef4, content=<a href='/topic/show?id=61f411e013b' target=_blank style='color:#2F92EE;'>#Micro#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11701, encryptionId=61f411e013b, topicName=Micro)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, 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createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2005410, encodeId=2c9a200541028, content=<a href='/topic/show?id=d09f155461e' target=_blank style='color:#2F92EE;'>#RNAs#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15546, encryptionId=d09f155461e, topicName=RNAs)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=05a2499, createdName=dzx0922889, createdTime=Tue Mar 10 02:45:00 CST 2015, time=2015-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=14953, encodeId=7e241495339, content=AKI is bad to person !, beContent=null, objectType=article, channel=null, level=null, likeNumber=168, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1aae1611537, createdName=loveios, createdTime=Mon Feb 02 15:37:00 CST 2015, time=2015-02-02, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1380469, encodeId=4b341380469d8, content=<a href='/topic/show?id=9281e34519b' target=_blank style='color:#2F92EE;'>#研究进展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=73451, encryptionId=9281e34519b, topicName=研究进展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f13d475, createdName=mashirong, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1396898, encodeId=dfd51396898d4, content=<a href='/topic/show?id=8bee565436d' target=_blank style='color:#2F92EE;'>#损伤#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=56543, encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
    2015-02-02 loveios

    AKI is bad to person !

    0

  9. 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createdName=xjy02, createdTime=Fri Nov 27 06:45:00 CST 2015, time=2015-11-27, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=42126, encodeId=246f421264f, content=管用 感觉对实验很有帮助 分析的很到位, beContent=null, objectType=article, channel=null, level=null, likeNumber=177, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=0eb81660032, createdName=angle宋琪, createdTime=Sun Nov 01 12:03:00 CST 2015, time=2015-11-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=33753, encodeId=459733e5378, content=如何少引起对别的器官的反应呢, beContent=null, objectType=article, channel=null, level=null, likeNumber=185, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3ykRSkuxjt93yc9tvDWfIQItrwiaKSCps5kyrTyDlwic2FgoCWe88wR3ZiaggKYGueDIp26zVgnbzriaQ/0, createdBy=89d71602869, createdName=sundong, createdTime=Wed Jul 29 11:11:00 CST 2015, time=2015-07-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=20248, encodeId=30be20248b2, content=轻度肾脏疾病对母亲和婴儿可能会增加孕期风险, beContent=null, objectType=article, channel=null, level=null, likeNumber=166, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20150920/IMG55FDE671A89482379.jpg, createdBy=cef3108336, createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=20249, encodeId=09b6202499c, content=轻度肾脏疾病对母亲和婴儿可能会增加孕期风险, beContent=null, objectType=article, channel=null, level=null, likeNumber=123, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20150920/IMG55FDE671A89482379.jpg, createdBy=cef3108336, createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2005410, encodeId=2c9a200541028, content=<a href='/topic/show?id=d09f155461e' target=_blank style='color:#2F92EE;'>#RNAs#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15546, encryptionId=d09f155461e, topicName=RNAs)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=05a2499, createdName=dzx0922889, createdTime=Tue Mar 10 02:45:00 CST 2015, time=2015-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=14953, encodeId=7e241495339, content=AKI is bad to person !, beContent=null, objectType=article, channel=null, level=null, likeNumber=168, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1aae1611537, 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encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
  10. [GetPortalCommentsPageByObjectIdResponse(id=1857342, encodeId=3830185e3426e, content=<a href='/topic/show?id=3f48525849' target=_blank style='color:#2F92EE;'>#CRO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5258, encryptionId=3f48525849, topicName=CRO)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c30265, createdName=jiafufeng@yaho, createdTime=Thu Jan 07 04:45:00 CST 2016, time=2016-01-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2084117, encodeId=7433208411ef4, content=<a href='/topic/show?id=61f411e013b' target=_blank style='color:#2F92EE;'>#Micro#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11701, encryptionId=61f411e013b, topicName=Micro)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, 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createdName=x35042875, createdTime=Sat Apr 11 22:22:00 CST 2015, time=2015-04-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2005410, encodeId=2c9a200541028, content=<a href='/topic/show?id=d09f155461e' target=_blank style='color:#2F92EE;'>#RNAs#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15546, encryptionId=d09f155461e, topicName=RNAs)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=05a2499, createdName=dzx0922889, createdTime=Tue Mar 10 02:45:00 CST 2015, time=2015-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=14953, encodeId=7e241495339, content=AKI is bad to person !, beContent=null, objectType=article, channel=null, level=null, likeNumber=168, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1aae1611537, 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encryptionId=8bee565436d, topicName=损伤)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4dfa37, createdName=智者为医08, createdTime=Sat Jan 31 00:45:00 CST 2015, time=2015-01-31, status=1, ipAttribution=)]
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