活性维生素D3通过nephrin-PI3KAkt信号通路对阿霉素肾病大鼠足细胞损伤的影响

前言(Introduction)慢性肾脏病(chronickidneydisease,CKD)是以肾实质的逐渐破坏和功能肾元的丧失为特点，最终导致终末期肾衰竭，以及各种病理条件的风险增加，包括心血管疾病和神经系统疾病，如冠状动脉钙化、高血压和中风等ADDINEN.CITE<EndNote><Cite><Author>Alam</Author><Year>2020</Year><RecNum>33</RecNum><DisplayText>[1]</DisplayText><record><rec-number>33</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">33</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Alam,M.A.</author><author>Nasiruddin,M.</author><author>Haque,S.F.</author><author>Khan,R.A.</author></authors></contributors><auth-address>DepartmentofPharmacology,JawaharlalNehruMedicalCollegeandHospital,AligarhMuslimUniversity,Aligarh,UttarPradesh,India. DepartmentofMedicine,JawaharlalNehruMedicalCollegeandHospital,AligarhMuslimUniversity,Aligarh,UttarPradesh,India.</auth-address><titles><title>EvaluationofsafetyandefficacyprofileofNigellasativaoilasanadd-ontherapy,inadditiontoalpha-ketoanalogueofessentialaminoacidsinpatientswithchronickidneydisease</title><secondary-title>SaudiJKidneyDisTranspl</secondary-title></titles><periodical><full-title>SaudiJKidneyDisTranspl</full-title></periodical><pages>21-31</pages><volume>31</volume><number>1</number><edition>2020/03/05</edition><dates><year>2020</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>32129194</accession-num><urls></urls><electronic-resource-num>10.4103/1319-2442.279943</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Alam,2020#33"1]。CKD是全球性疾病，在2013年的全球疾病负担研究中，估计有95万人死于CKD，迄今，世界范围内，终末期肾病（ESRD）已达140万余人，CKD成为全球公共卫生重点ADDINEN.CITE<EndNote><Cite><Year>2015</Year><RecNum>82</RecNum><DisplayText>[2,3]</DisplayText><record><rec-number>82</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">82</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors></contributors><titles><title>Global,regional,andnationalage-sexspecificall-causeandcause-specificmortalityfor240causesofdeath,1990-2013:asystematicanalysisfortheGlobalBurdenofDiseaseStudy2013</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>117-71</pages><volume>385</volume><number>9963</number><edition>2014/12/23</edition><dates><year>2015</year><pub-dates><date>Jan10</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>25530442</accession-num><urls></urls><custom2>Pmc4340604</custom2><electronic-resource-num>10.1016/s0140-6736(14)61682-2</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite><Cite><Year>2017</Year><RecNum>83</RecNum><record><rec-number>83</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">83</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors></contributors><titles><title>KidneyDisease:ImprovingGlobalOutcomes(KDIGO)CKD-MBDUpdateWorkGroup.KDIGO2017ClinicalPracticeGuidelineUpdatefortheDiagnosis,Evaluation,Prevention,andTreatmentofChronicKidneyDisease–MineralandBoneDisorder(CKD-MBD).KidneyIntSuppl.2017;7:1–59</title><secondary-title>KidneyInternationalSupplements</secondary-title></titles><periodical><full-title>KidneyInternationalSupplements</full-title></periodical><volume>7</volume><number>3</number><dates><year>2017</year></dates><isbn>2157-1716</isbn><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[\o",2015#82"2,\o",2017#83"3]。导致CKD进展的因素包括实质细胞丢失、慢性炎症、纤维化和肾再生能力降低等，目前，关于CKD的防治成为中国肾脏病学术界最活跃的一个研究领域，但肾病学的研究证据相对有限，具体的发病机制尚不十分清楚ADDINEN.CITE<EndNote><Cite><Author>Peev</Author><Year>2017</Year><RecNum>30</RecNum><DisplayText>[4]</DisplayText><record><rec-number>30</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">30</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Peev,V.</author><author>Hahm,E.</author><author>Reiser,J.</author></authors></contributors><auth-address>DepartmentofInternalMedicine,RushUniversityMedicalCenter,Chicago,IL,USA.</auth-address><titles><title>Unwindingfocalsegmentalglomerulosclerosis</title><secondary-title>F1000Res</secondary-title></titles><periodical><full-title>F1000Res</full-title></periodical><pages>466</pages><volume>6</volume><edition>2017/05/12</edition><dates><year>2017</year></dates><isbn>(Electronic) (Linking)</isbn><accession-num>28491286</accession-num><urls></urls><custom2>Pmc5399957</custom2><electronic-resource-num>10.12688/f1000research.10510.1</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Peev,2017#30"4]。我们都知道，现在CKD的有效治疗还未满足的医疗需求，因此，寻求CKD预防和治疗手段迫在眉睫。足细胞，高度分化的极性腺上皮细胞，有膜延伸，以高度极化的方式在基底膜上分枝，关于足细胞生物学研究有望帮助人们更好地理解与蛋白尿相关的多种疾病的机械性质，涉及足细胞上皮细胞功能，包括足细胞足突功能减退等ADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2019</Year><RecNum>31</RecNum><DisplayText>[5]</DisplayText><record><rec-number>31</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">31</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,H.</author><author>Zhang,Y.</author><author>Xia,F.</author><author>Zhang,W.</author><author>Chen,P.</author><author>Yang,G.</author></authors></contributors><auth-address>DepartmentofNephrology,TheFirstAffiliatedHospitalofBaotouMedicalCollegeInnerMongoliaUniversityofScienceandTechnology,Baotou,China. DepartmentofNephrology,NorthHospital,Baotou,China. CentralLaboratory,TheFirstAffiliatedHospitalofBaotouMedicalCollegeInnerMongoliaUniversityofScienceandTechnology,No.41LinyinRoad,KundulunDistrict,Baotou,014010,InnerMongolia,China. DepartmentofNutriology,TheFirstAffiliatedHospitalofBaotouMedicalCollegeInnerMongoliaUniversityofScienceandTechnology,Baotou,China. CentralLaboratory,TheFirstAffiliatedHospitalofBaotouMedicalCollegeInnerMongoliaUniversityofScienceandTechnology,No.41LinyinRoad,KundulunDistrict,Baotou,014010,InnerMongolia,China.guoany_yangga@163.com.</auth-address><titles><title>ProtectiveeffectofsilencingStat1onhighglucose-inducedpodocytesinjuryviaForkheadtranscriptionfactorO1-regulatedtheoxidativestressresponse</title><secondary-title>BMCMolCellBiol</secondary-title></titles><periodical><full-title>BMCMolCellBiol</full-title></periodical><pages>27</pages><volume>20</volume><number>1</number><edition>2019/07/25</edition><dates><year>2019</year><pub-dates><date>Jul23</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>31337338</accession-num><urls></urls><electronic-resource-num>10.1186/s12860-019-0209-0</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Wang,2019#31"5]。足细胞骨架的改变和迁移特性与蛋白尿和肾小球硬化的发展之间存在着很强的相关性ADDINEN.CITE<EndNote><Cite><Author>Canaud</Author><Year>2013</Year><RecNum>81</RecNum><DisplayText>[6]</DisplayText><record><rec-number>81</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">81</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Canaud,G.</author><author>Bienaimé,F.</author><author>Viau,A.</author><author>Treins,C.</author><author>Baron,W.</author><author>Nguyen,C.</author><author>Burtin,M.</author><author>Berissi,S.</author><author>Giannakakis,K.</author><author>Muda,A.O.</author><author>Zschiedrich,S.</author><author>Huber,T.B.</author><author>Friedlander,G.</author><author>Legendre,C.</author><author>Pontoglio,M.</author><author>Pende,M.</author><author>Terzi,F.</author></authors></contributors><auth-address>1]InstitutNationaldelaSantéetdelaRechercheMédicale(INSERM)U845,CentredeRecherche'CroissanceetSignalisation',UniversitéParisDescartes,SorbonneParisCité,HôpitalNecker-EnfantsMalades,Paris,France.[2]ServicedeNéphrologieTransplantationAdultes,HôpitalNecker-EnfantsMalades,Paris,France.[3].</auth-address><titles><title>AKT2isessentialtomaintainpodocyteviabilityandfunctionduringchronickidneydisease</title><secondary-title>Nat.Med.</secondary-title></titles><periodical><full-title>Nat.Med.</full-title></periodical><pages>1288-96</pages><volume>19</volume><number>10</number><edition>2013/09/24</edition><dates><year>2013</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>24056770</accession-num><urls></urls><electronic-resource-num>10.1038/nm.3313</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Canaud,2013#81"6]。最近的足细胞生物学和基因破坏研究表明，单个足细胞分子的异常与蛋白尿和肾小球硬化之间存在因果关系ADDINEN.CITE<EndNote><Cite><Author>Huang</Author><Year>2019</Year><RecNum>42</RecNum><DisplayText>[7]</DisplayText><record><rec-number>42</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">42</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Huang,H.</author><author>Fan,Y.</author><author>Gao,Z.</author><author>Wang,W.</author><author>Shao,N.</author><author>Zhang,L.</author><author>Yang,Y.</author><author>Zhu,W.</author><author>Chen,Z.</author><author>Hu,J.</author><author>Ding,G.</author></authors></contributors><auth-address>DivisionofNephrology,RenminHospitalofWuhanUniversity,Wuhan,430060,Hubei,China. DivisionofRehabilitation,TianmenFirstPeople'sHospital,Tianmen,Hubei,China. DivisionofNephrology,RenminHospitalofWuhanUniversity,Wuhan,430060,Hubei,China.ghxding@.</auth-address><titles><title>HIF-1αcontributestoAngII-inducedinflammatorycytokineproductioninpodocytes</title><secondary-title>BMCPharmacolToxicol</secondary-title></titles><periodical><full-title>BMCPharmacolToxicol</full-title></periodical><pages>59</pages><volume>20</volume><number>1</number><edition>2019/10/19</edition><dates><year>2019</year><pub-dates><date>Oct17</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>31623681</accession-num><urls></urls><electronic-resource-num>10.1186/s40360-019-0340-8</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Huang,2019#42"7]。结蛋白(desmin)是一种细胞骨架中间的丝蛋白成分，其特殊的连接收缩保持了细胞结构和机械完整性，其表达上调在疾病发病过程中维持正常肌层排列的一种防御机制ADDINEN.CITE<EndNote><Cite><Author>White</Author><Year>2004</Year><RecNum>34</RecNum><DisplayText>[8]</DisplayText><record><rec-number>34</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">34</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>White,K.E.</author><author>Bilous,R.W.</author></authors></contributors><auth-address>SchoolofClinicalMedicalStudies,MedicalSchool,UniversityofNewcastleuponTyne,NE24HH,UK.k.e.white@ncl.ac.uk</auth-address><titles><title>Structuralalterationstothepodocytearerelatedtoproteinuriaintype2diabeticpatients</title><secondary-title>Nephrol.Dial.Transplant.</secondary-title></titles><periodical><full-title>Nephrol.Dial.Transplant.</full-title></periodical><pages>1437-40</pages><volume>19</volume><number>6</number><edition>2004/03/03</edition><dates><year>2004</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>14993494</accession-num><urls></urls><electronic-resource-num>10.1093/ndt/gfh129</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"White,2004#34"8]。desmin免疫反应是一种有效、敏感的急性足细胞损伤指标，对肾小球损伤有潜在的疗效标志和足细胞损伤的毒性标志作用。体内体外研究表明，大量肾脏疾病小鼠受损足细胞的结蛋白增加，提示结蛋白参与足细胞损伤ADDINEN.CITE<EndNote><Cite><Author>Chen</Author><Year>2018</Year><RecNum>43</RecNum><DisplayText>[9]</DisplayText><record><rec-number>43</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">43</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Chen,Y.N.</author><author>Wu,C.G.</author><author>Shi,B.M.</author><author>Qian,K.</author><author>Ding,Y.</author></authors></contributors><auth-address>DepartmentofGeriatrics,TheThirdAffiliatedHospitalofSoochowUniversityJiangsu,China. DepartmentofEndocrinology,TheAffiliatedPeople'sHospitalofJiangsuUniversityChina. DepartmentofEndocrinology,TheFirstAffiliatedHospitalofSoochowUniversityJiangsu,China.</auth-address><titles><title>Theprotectiveeffectofasiaticacidonpodocytesinthekidneyofdiabeticrats</title><secondary-title>AmJTranslRes</secondary-title></titles><periodical><full-title>AmJTranslRes</full-title></periodical><pages>3733-3741</pages><volume>10</volume><number>11</number><edition>2019/01/22</edition><dates><year>2018</year></dates><isbn>(Electronic) (Linking)</isbn><accession-num>30662623</accession-num><urls></urls><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Chen,2018#43"9]。研究足细胞的损伤有望帮助人们更好地理解与蛋白尿相关的多种疾病的机械性质。附着在肾小球基底膜(GBM)的肾小球毛细血管上足突，彼此相连，形成隔膜ADDINEN.CITE<EndNote><Cite><Author>Ichimura</Author><Year>2007</Year><RecNum>32</RecNum><DisplayText>[10]</DisplayText><record><rec-number>32</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">32</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Ichimura,K.</author><author>Kurihara,H.</author><author>Sakai,T.</author></authors></contributors><auth-address>DepartmentofAnatomy,JuntendoUniversitySchoolofMedicine,2-1-1Hongo,Bunkyo-ku,Tokyo113-8421,Japan.ichimura@med.juntendo.ac.jp</auth-address><titles><title>Actinfilamentorganizationoffootprocessesinvertebrateglomerularpodocytes</title><secondary-title>CellTissueRes.</secondary-title></titles><periodical><full-title>CellTissueRes.</full-title></periodical><pages>541-57</pages><volume>329</volume><number>3</number><edition>2007/07/03</edition><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>17605050</accession-num><urls></urls><electronic-resource-num>10.1007/s00441-007-0440-4</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Ichimura,2007#32"10]。Nephrin是位于狭缝横膈膜的免疫球蛋白超家族的跨膜蛋白原，是维持肾小球滤过膜的渗透不可或缺的，与其他足细胞分子CD2相关蛋白（CD2AP）、膜蛋白（podocin）、闭锁连接蛋白-1(ZO-1)等并介导重要的细胞信号ADDINEN.CITE<EndNote><Cite><Author>Martin</Author><Year>2018</Year><RecNum>35</RecNum><DisplayText>[11]</DisplayText><record><rec-number>35</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">35</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Martin,C.E.</author><author>Jones,N.</author></authors></contributors><auth-address>DepartmentofMolecularandCellularBiology,UniversityofGuelph,Guelph,ON,Canada.</auth-address><titles><title>NephrinSignalinginthePodocyte:AnUpdatedViewofSignalRegulationattheSlitDiaphragmandBeyond</title><secondary-title>FrontEndocrinol(Lausanne)</secondary-title></titles><periodical><full-title>FrontEndocrinol(Lausanne)</full-title></periodical><pages>302</pages><volume>9</volume><edition>2018/06/21</edition><dates><year>2018</year></dates><isbn>(Electronic) (Linking)</isbn><accession-num>29922234</accession-num><urls></urls><custom2>Pmc5996060</custom2><electronic-resource-num>10.3389/fendo.2018.00302</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Martin,2018#35"11]。nephrin是形成SD重要的分子筛，能识别血液的过滤防止过滤过程中必需，足细胞任何一种结构的破坏或nephrin丢失/减少是足细胞上皮特征的丧失，加重诸如微小病变、局灶性节段性肾小球硬化和糖尿病肾病等蛋白尿性疾病ADDINEN.CITE<EndNote><Cite><Author>Schell</Author><Year>2014</Year><RecNum>36</RecNum><DisplayText>[12]</DisplayText><record><rec-number>36</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">36</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Schell,C.</author><author>Wanner,N.</author><author>Huber,T.B.</author></authors></contributors><auth-address>RenalDivision,UniversityMedicalCenterFreiburg,Germany;SpemannGraduateSchoolofBiologyandMedicine(SGBM),AlbertLudwigsUniversityFreiburg,Germany;FacultyofBiology,AlbertLudwigsUniversityFreiburgGermany. RenalDivision,UniversityMedicalCenterFreiburg,Germany. RenalDivision,UniversityMedicalCenterFreiburg,Germany;SpemannGraduateSchoolofBiologyandMedicine(SGBM),AlbertLudwigsUniversityFreiburg,Germany;FacultyofBiology,AlbertLudwigsUniversityFreiburgGermany;BIOSSCenterforBiologicalSignallingStudies,Albert-Ludwigs-UniversityFreiburg,Germany.Electronicaddress:tobias.huber@uniklinik-freiburg.de.</auth-address><titles><title>Glomerulardevelopment--shapingthemulti-cellularfiltrationunit</title><secondary-title>Semin.CellDev.Biol.</secondary-title></titles><periodical><full-title>Semin.CellDev.Biol.</full-title></periodical><pages>39-49</pages><volume>36</volume><edition>2014/08/26</edition><dates><year>2014</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>25153928</accession-num><urls></urls><electronic-resource-num>10.1016/j.semcdb.2014.07.016</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"Schell,2014#36"12]。HeM等ADDINEN.CITE<EndNote><Cite><Author>He</Author><Year>2019</Year><RecNum>40</RecNum><DisplayText>[13]</DisplayText><record><rec-number>40</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">40</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>He,M.</author><author>Wang,J.</author><author>Yin,Z.</author><author>Zhao,Y.</author><author>Hou,H.</author><author>Fan,J.</author><author>Li,H.</author><author>Wen,Z.</author><author>Tang,J.</author><author>Wang,Y.</author><author>Wang,D.W.</author><author>Chen,C.</author></authors></contributors><auth-address>,430030,DivisionofCardiologyandHubeiKeyLaboratoryofGeneticsandMolecularMechanismsofCardiologicalDisorders,TongjiHospital,TongjiMedicalCollege,HuazhongUniversityofScienceandTechnology,Wuhan430030,China.</auth-address><titles><title>MiR-320ainducesdiabeticnephropathyviainhibitingMafB</title><secondary-title>Aging(AlbanyNY)</secondary-title></titles><periodical><full-title>Aging(AlbanyNY)</full-title></periodical><edition>2019/05/19</edition><dates><year>2019</year><pub-dates><date>May17</date></pub-dates></dates><isbn>(Electronic) (Linking)</isbn><accession-num>31102503</accession-num><urls></urls><electronic-resource-num>10.18632/aging.101962</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider></record></Cite></EndNote>[\o"He,2019#40"13]发现Nephrin下调是加重糖尿病肾病（DN）的肾功能障碍。LiuM等ADDINEN.CITEADDINEN.CITE.DATA[\o"Liu,2017#37"14]发现发现在足细胞肾病期间，尿激酶纤溶酶原激活物受体（uPAR）的激活事件发生由于nephrin表达的丧失，也是导致足细胞足突消退和蛋白尿发生发展所必需的。郭晓媛ADDINEN.CITE<EndNote><Cite><Author>郭晓媛</Author><Year>2019</Year><RecNum>38</RecNum><DisplayText>[15]</DisplayText><record><rec-number>38</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">38</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>郭晓媛</author><author>王暴魁</author><author>谢璇</author><author>蔡倩</author><author>孙广宇</author><author>雷明</author><author>宋子威</author><author>王健</author></authors></contributors><auth-address>北京中医药大学东方医院肾病科;北京中医药大学;</auth-address><titles><title>扶正祛风方对膜性肾病大鼠肾组织nephrin和TGF-β_1表达的影响</title><secondary-title>中国中西医结合肾病杂志</secondary-title></titles><periodical><full-title>中国中西医结合肾病杂志</full-title></periodical><pages>290-292</pages><volume>20</volume><number>04</number><keywords><keyword>膜性肾病</keyword><keyword>足细胞</keyword><keyword>扶正祛风</keyword></keywords><dates><year>2019</year></dates><isbn>1009-587X</isbn><call-num>14-1277/R</call-num><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[\o"郭晓媛,2019#38"15]在膜性肾病大鼠同样观察到nephrin蛋白表达的下调。唐英等ADDINEN.CITE<EndNote><Cite><Author>唐英</Author><Year>2018</Year><RecNum>39</RecNum><DisplayText>[16]</DisplayText><record><rec-number>39</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">39</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>唐英</author><author>蒋宇锋</author><author>曹和欣</author><author>张昕贤</author><author>何立群</author></authors></contributors><auth-address>上海中医药大学附属曙光医院;</auth-address><titles><title>基于玄府理论的固本通络方对IgA肾病大鼠Nephrin和CD_2AP表达的影响</title><secondary-title>中国中西医结合肾病杂志</secondary-title></titles><periodical><full-title>中国中西医结合肾病杂志</full-title></periodical><pages>388-390</pages><volume>19</volume><number>05</number><keywords><keyword>固本通络方</keyword><keyword>IgA肾病</keyword><keyword>足细胞</keyword><keyword>Nephrin</keyword><keyword>CD2AP</keyword></keywords><dates><year>2018</year></dates><isbn>1009-587X</isbn><call-num>14-1277/R</call-num><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[\o"唐英,2018#39"16]研究表明固本通络方调控Nephrin、CD2AP的表达上调，从而有效减轻IgA大鼠蛋白尿及肾小球病变。应该注意的是，外隔膜蛋白nephrin,CD2AP,podocin不仅是细胞外SD滤过网络的核心成分，还是细胞内短区的相互作用的信号支架，然而CKD与nephrin调控下潜在机制尚未完全阐明，研究nephrin在活性维生素D3治疗CKD的信号作用具有重要的临床现实意义。磷脂酰肌醇-3-激酶/蛋白激酶B(PI3K/Akt)信号通路是研究细胞周期调控的热点网络，它对细胞生长、代谢和死亡等多个关键环节有着广泛的影响ADDINEN.CITEADDINEN.CITE.DATA[\o"Mirza-Aghazadeh-Attari,2020#44"17]。研究发现，外隔膜蛋白nephrin、CD2AP，podocin除了对肾小球足细胞（即肾脏肾小球上皮细胞）的完整性至关重要外，还能够启动肾小球足细胞PI3K/Akt依赖的信号转导ADDINEN.CITE<EndNote><Cite><Author>B</Author><Year>2003</Year><RecNum>45</RecNum><DisplayText>[18]</DisplayText><record><rec-number>45</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">45</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>HuberTobiasB</author><author>HartlebenBjörn</author><author>KimJeong</author><author>SchmidtsMiriam</author><author>SchermerBernhard</author><author>KeilAlexander</author><author>EggerLotti</author><author>LechaRachelL</author><author>BornerChristoph</author><author>PavenstädtHermann</author><author>ShawAndreyS</author><author>WalzGerd</author><author>BenzingThomas</author></authors></contributors><auth-address>RenalDivision.MolecularMedicine,UniversityHospitalFreiburg,D-79106Freiburg,Germany.</auth-address><titles><title>NephrinandCD2APassociatewithphosphoinositide3-OHkinaseandstimulateAKT-dependentsignaling</title><secondary-title>Molecularandcellularbiology</secondary-title></titles><periodical><full-title>Molecularandcellularbiology</full-title></periodical><volume>23</volume><number>14</number><dates><year>2003</year></dates><isbn>0270-7306</isbn><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[\o"B,2003#45"18]。先前的众多研究强调了PI3K/Akt与抗肾脏炎症、抑制足细胞功能障碍所发挥的作用，一些学者也PI3K/Akt作为nephrin下游这一存在的说法ADDINEN.CITEADDINEN.CITE.DATA[\o"Lu,2019#46"19,\o"Wei-Jian,2019#47"20]。nephrin-CD2AP-p85复合体的存在也被发现，体外孤立的肾小球中也证明nephrin与PI3K的p85管理子单元相关联，相似的相互功能也被报道在体外调节肾足细胞的功能ADDINEN.CITE<EndNote><Cite><Author>Thomas</Author><Year>2004</Year><RecNum>48</RecNum><DisplayText>[21]</DisplayText><record><rec-number>48</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">48</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>BenzingThomas</author></authors></contributors><auth-address>RenalDivision,UniversityHospitalFreiburg,Hugstetterstrassse55,79106Freiburg,Germany.benzing@med1.ukl.uni-freiburg.de</auth-address><titles><title>Signalingattheslitdiaphragm</title><secondary-title>JournaloftheAmericanSocietyofNephrology:JASN</secondary-title></titles><periodical><full-title>JournaloftheAmericanSocietyofNephrology:JASN</full-title></periodical><volume>15</volume><number>6</number><dates><year>2004</year></dates><isbn>1046-6673</isbn><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite></EndNote>[\o"Thomas,2004#48"21]。关于nephrin联合PI3K对下游Akt激活，类似蛋白的磷酸化的激活，有研究发现nephrin自身磷酸化调节相互作用领域与一些蛋白质相互作用，不仅仅依靠于nephrin-podocin-CD2AP复合体，还包括PI3K等一些通路分子蛋白，从而发挥细胞调控功能ADDINEN.CITE<EndNote><Cite><Author>B</Author><Year>2001</Year><RecNum>50</RecNum><DisplayText>[22,23]</DisplayText><record><rec-number>50</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">50</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>HuberTB</author><author>KottgenM</author><author>SchillingB</author><author>WalzG</author><author>BenzingT</author></authors></contributors><auth-address>RenalDivision,UniversityHospitalFreiburg,Freiburg79106,Germany.</auth-address><titles><title>Interactionwithpodocinfacilitatesnephrinsignaling</title><secondary-title>TheJournalofbiologicalchemistry</secondary-title></titles><periodical><full-title>TheJournalofbiologicalchemistry</full-title></periodical><volume>276</volume><number>45</number><dates><year>2001</year></dates><isbn>0021-9258</isbn><urls></urls><remote-database-provider>Cnki</remote-database-provider></record></Cite><Cite><Author>Sanna</Author><Year>2002</Year><RecNum>49</RecNum><record><rec-number>49</rec-number><foreign-keys><keyapp="EN"db-id="r5t22vsvzev5r8ezx93vd994vvrdt52pdd5z">49</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>LehtonenSanna</author><author>ZhaoFang</author><author>LehtonenEero</author></authors></contributors><auth-address>DepartmentofPathology,HaartmanInstituteandHelsinkiUniversityCentralHospital,UniversityofHelsinki,Finland.</auth-address><titles><title>CD2-associated