| 英文摘要Taiwanhasthehighestincidenceandprevalenceofdialysisintheworld,andthesecauselargeburdenofmedicalresourcesandpublichealth.Thetherapeutictargetsinnephrologyarethereductionofinjury,thedelayofprogression,orrenalreplacementtherapyconsistingofeitherrenaltransplantationordialysis.Interstitialfibrosishasamajorroleintheprogressionofrenaldiseases.Severalanimalmodelsareavailableforthestudyofrenalfibrosis.Unilateralureteralobstruction(UUO)hasemergedasanimportantmodelforthestudyofrenalfibrosis.Manyquantifiablepathophysiologicaleventsoccuroverthespanof1wkofUUO,makingthisanattractivemodelforthestudyofthemechanismsofrenalinterstitialfibrosisandtheevaluationofpotentialtherapeuticapproachestoamelioratethefibrosis.UUOresultsinchangesinrenalhemodynamics,infiltrationofthekidneybymacrophages,andsubsequentfibrosisofthetubulointerstitium.Recentstudiesdemonstratedthatinflammationandoxidativestressplaysignificantroleinrenalfibrosis.Therefore,agentswithanti-inflammatoryandanti-oxidativepropertyhaveapotentialtherapeuticeffectsontheprogressionofUUO.DMiswidelyusedclinicallyasanonopioidantitussive.However,theexactmechanismofitssoughsuppressionactionremainsunclear.DMhasbeenshowntobeneuroprotectiveinseveralanimalneurodegenerativemodelsandaLPS-inducedendotoxemiamodelthroughinhibitionoftheinhibitionofNADPHoxidase,suggestingDMshavestronganti-inflammatoryandant-oxidationproperty.Sinceoxidativestressandinflammation,whichmaybeduetotheactivationofrenalNADPHoxidase,arecentralfeaturesofUUO,itispossiblethatDMsmayhavetherapeuticeffectsontherenalfibrosisofUUO.Inthisstudy,IexaminedwhetheradecreaseintheproductionofcytokineoroxidativestressisinvolvedinthebeneficialeffectsofDMsinanimalswithUUO.Currentmedicaltreatments,however,cannoteffectivelycontroltheprogressionofchronickidneydiseases(CKD),anditisurgenttodevelopnoveltreatmentmodalityforprogressiverenalfibrosis.Newtherapeuticstrategiesfortissuerepairhaveemergedandoneofthemostpromisingapproachesistheuseofstemcellstoreduceinjuryfollowingatoxic/ischemiceventortopreventchronickidneydisease.Itisshownbyafewresearchersthatmesenchymalstemcells(MSCs)arerenotropicandimprovefunctioninacuterenalfailure(ARF).ItisalsoreportedthatMSCsreduceinterstitialfibrosis,butdonotdelaytheprogressionofchronickidneydisease(CKD).Recently,thestudygroupleadbyProf.TangMing-JerinNCKUhasisolatedtherenalprogenitorcellsMKPCs(mousekidneyprogenitorcells)fromthekidneyofmyosinheavychain9-GFPtransgenicmiceandtheMKPCscellscanreducetheseverityofischemia-reperfusioninjurywheninjectedintotherenalparenchyma.AnotherimportantissueistheuseofMKPCsforrenalfibrosis.InsubsequentstudyinTaiwan,IhypothesizethatMKPCsmaybeusedfortreatingtherenalfibrosisofCKD.MygoalsaretoinvestigatewhetherthetreatmentwithMKPCscanpreserverenalfunctionandattenuateinjuryinvitro(co-culturedrenalepithelialcellswithMKPCscellsintubulogenesisandTGFβinducedepithelial-mesenchymatransition[EMT])andinvivo(infusionofMKPCscellstotheSCIDmiceundergoingunilateraluretericligation[UUO]). |