title: Multidrug resistance-related protein 2 genotype of the donor affects kidney graft function.
abstract: OBJECTIVE
  We tested the effect of kidney-specific multidrug resistance-related protein (MRP2, ABCC2) deficiency on renal organic solute disposition as well as on renal protein and gene expression. Furthermore, we investigated whether a particular kidney donor ABCC2 genotype is associated with delayed graft function in patients.
  
  
  METHODS
  A new MRP2-deficient rat strain was established. Renal cross-transplantations were performed between congenic MRP2-deficient and wild-type rats. Renal disposition of MRP2 substrates was investigated in native and transplanted rats. Proteomic analyses and transcriptional profiling were performed in rat kidney graft cortices. Ninety-eight human kidney donor-recipient pairs were genotyped for five ABCC2 polymorphisms. The relationship between delayed graft function and ABCC2 genetic variants in donors and recipients was analyzed by backward stepwise logistic regression.
  
  
  RESULTS
  In rats, the absence of renal MRP2 reduced renal bilirubin glucuronide excretion at pathologic plasma concentrations, modified renal p-aminohippurate excretion and did not affect renal morphine-6-glucuronide excretion. Renal MRP2 deficiency led to renal cortical protein or mRNA upregulation of glutathione transferase isoenzymes, glutaredoxin 2, and heme oxygenase-1. In patients, a particular donor ABCC2 genotype was associated with an increased incidence of delayed graft function.
  
  
  CONCLUSIONS
  Kidney graft-specific MRP2 deficiency has mild effects on the renal excretion of some organic solutes under experimental conditions and induces a protein and gene expression pattern indicative of activated antioxidant defense mechanisms. This suggests that MRP2 is a determinant of the redox status in tubular epithelial cells and thus of the susceptibility to renal damage under conditions of treatment with multiple drugs and increased oxygen radical formation.
authors.affiliation: Institute of Physiology, University of Greifswald, Karlsburg, Germany. grisko@uni-greifswald.de
authors.forename: Olaf
authors.initials: O
authors.lastname: Grisk
authors.forename: Antje C
authors.initials: AC
authors.lastname: Steinbach
authors.forename: Sabine
authors.initials: S
authors.lastname: Ciecholewski
authors.forename: Torsten
authors.initials: T
authors.lastname: Schlüter
authors.forename: Ingrid
authors.initials: I
authors.lastname: Klöting
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Eike
authors.initials: E
authors.lastname: Dazert
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Leif
authors.initials: L
authors.lastname: Steil
authors.forename: Stefan
authors.initials: S
authors.lastname: Gauer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jedlitschky
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Ingeborg A
authors.initials: IA
authors.lastname: Hauser
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Rainer
authors.initials: R
authors.lastname: Rettig
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D020869:Gene Expression Profiling; D014644:Genetic Variation; D005838:Genotype; D054477:Glutaredoxins / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D016030:Kidney Transplantation; D016015:Logistic Models; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency* / Q000235:genetics; D011110:Polymorphism, Genetic; D020543:Proteome / Q000032:analysis; D040901:Proteomics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014019:Tissue Donors; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D054477:Glutaredoxins; D005982:Glutathione Transferase; D051547:Heme Oxygenase-1; D007527:Isoenzymes; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020543:Proteome; D012333:RNA, Messenger; C000715087:ABCC2 protein, human