Pfaller_and_Gstraunthaler_1998

Pfaller_and_Gstraunthaler_1998 -...

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Unformatted text preview: NephrotoxicityTestinginVitro-What W e Know andWhat W e Need to Know WalterPfallerandGerhardGstraunthaler InstituteofPhysiology,UniversityofInnsbruck,Innsbruck,Austria Thekidneyisaffectedbymany chemicals.Some ofthechemicalsmay even contributetoend- stage renaldiseaseand thus contributeconsiderablyto healthcare costs. Because ofthe large functional reserve ofthe kidney, which masks signsofdysfunction, earlydiagnosisofrenal disease isoften difficult.Although numerous studiesaimed at understandingthe mechanisms underlying chemicals and drugs thattargetvarious renal celltypes have delivered enough understandingfora reasonableriskassessment, thereisstillan urgent needtobetterunderstand themechanisms leadingto renalcellinjuryand organ dysfunction.The increasinguse ofinvitro techniques using isolatedrenalcells,nephron fragments, or cellculturesderivedfrom specific renalcelltypeshasimprovedour insightintothemolecularmechanismsinvolvedinnephrotoxicity. A shortoverviewisgiven on thevarious invitrosystems currentlyused to clarifymechanistic aspects leadingto sublethalor lethal injuryofthefunctionally most importantnephronepithelial cellsderivedfromvariousspecies.Whereas freshlyisolatedcellsand nephronfragments appear to represent a sufficient basis to studyacute effects (hours)of nephrotoxins, e.g., on cell metabolism, primaryculturesofthese cellsare more appropriate to study long-term effects. In contrast to isolatedcellsand fragments, however, primaryculturestend to firstloseseveral of theirinvivometabolicpropertiesduringculture,andsecondtohaveonlya limitedlife span (days to weeks). Moreover, establishingsuch primarycultures isa time-consuming and laborious procedure.Forthatreason many studieshavebeen carriedout on renalcelllines,which are easy to cultivateinlargequantitiesand which have an unlimited lifespan. Unfortunately, none ofthe linesdisplaya stateofdifferentiationcomparabletothatoffreshlyisolatedcellsor theirprimary cultures.Mostoftentheylackexpressionofkeyfunctions(e.g.,gluconeogenesisororganicanion transport) oftheirinvivocorrespondents. Therefore, the use ofcelllinesforassessment of nephrotoxicmechanismswillbelimitedtothosefunctionsthelinesexpress. Upcoming molecular biologyapproachessuchas thetransductionofimmortalizinggenes intoprimaryculturesandthe utilizationofcellsfromtransgenicanimals may inthenear futureresultintheavailabilityofhighly differentiated renalcellswith markedlyextended life spans and near invivocharacteristicsthat may facilitatethe use ofrenalcellcultureforroutinescreeningofnephrotoxins.- EnvironHealth Perspect106(Suppl 2):559-569 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-2/ 559-569pfaller/abstract.html Keywords: nephrotoxicity,xenobiotics,invitrotests, renalcellculture Introduction Exposuretodrugsandchemicalsoften resultsintoxicityto livingorganisms. We mustrecognizethefactthatnotallcom- poundsareequallytoxictoallpartsofa livingsystembecausethetoxicactionsof manycompounds aremanifestedinspe- cificorgans.Theseorgansareknown ascificorgans....
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This note was uploaded on 02/10/2012 for the course PHY 495 taught by Professor Hess during the Summer '11 term at Alabama.

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Pfaller_and_Gstraunthaler_1998 -...

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