Multidrug resistance-related protein 2 genotype of the donor affects kidney graft function.

Abstract:

OBJECTIVES: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. CONCLUSION: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.

journal_name

Pharmacogenet Genomics

authors

Grisk O,Steinbach AC,Ciecholewski S,Schlüter T,Klöting I,Schmidt H,Dazert E,Schaeffeler E,Steil L,Gauer S,Jedlitschky G,Schwab M,Geisslinger G,Hauser IA,Völker U,Kroemer HK,Rettig R

doi

10.1097/FPC.0b013e328328d4e9

subject

Has Abstract

pub_date

2009-04-01 00:00:00

pages

276-88

issue

4

eissn

1744-6872

issn

1744-6880

journal_volume

19

pub_type

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