Multidrug resistance-related protein 2 genotype of the donor affects kidney graft function.
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.
Grisk
Olaf
O
Institute of Physiology, University of Greifswald, Karlsburg, Germany. grisko@uni-greifswald.de
Steinbach
Antje C
AC
Ciecholewski
Sabine
S
Schlüter
Torsten
T
Klöting
Ingrid
I
Schmidt
Helmut
H
Dazert
Eike
E
Schaeffeler
Elke
E
Steil
Leif
L
Gauer
Stefan
S
Jedlitschky
Gabriele
G
Schwab
Matthias
M
Geisslinger
Gerd
G
Hauser
Ingeborg A
IA
Völker
Uwe
U
Kroemer
Heyo K
HK
Rettig
Rainer
R
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
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