title: Kidney-specific deletion of multidrug resistance-related protein 2 does not aggravate acute cyclosporine A nephrotoxicity in rats.
abstract: OBJECTIVE
  Multidrug resistance-related protein 2 (Mrp2) is expressed in apical membranes of renal proximal tubular cells and contributes to the renal secretion of cyclosporine A (CsA). Mrp2⁻/⁻ deficiency may lead to local renal CsA accumulation. We investigated whether kidney-specific Mrp2 deficiency enhances acute CsA nephrotoxicity in rats.
  
  
  METHODS
  Kidney-specific Mrp2 deletion was achieved by bilateral nephrectomy and transplantation of a congenic Mrp2-deficient kidney into wild-type recipients. Controls received a wild-type kidney. Animals were treated with CsA (10 or 30 mg/kg/day) for 7 days. Renal hemodynamics and renal cortical mRNA expression profile, oxidative stress, and the abundance of multidrug resistance protein 1 (Mdr1) and Mrp2 were assessed.
  
  
  RESULTS
  CsA accumulation and CsA-induced reduction in glomerular filtration rate were similar in wild-type and Mrp2⁻/⁻ kidneys. Renal vascular resistance and agonist-induced renal vascular responses were similar in both groups. A PCR array on 84 genes involved in the biotransformation and antioxidant defense revealed increased CsA-induced mRNA expression of genes involved in oxidative and metabolic stress, inflammation, and apoptosis. This gene expression pattern was similar in wild-type and Mrp2⁻/⁻ kidneys. CsA increased the renal cortical oxidized glutathione, did not affect xanthine oxidase-dependent superoxide formation, and decreased renal cortical NADPH oxidase-dependent superoxide formation. Furthermore, CsA increased Mdr1 protein abundance to a greater extent in Mrp2⁻/⁻ than in wild-type kidneys.
  
  
  CONCLUSIONS
  Mrp2 is not critical for renal CsA disposition and its deficiency does not enhance acute CsA nephrotoxicity. The high Mdr1 abundance may at least in part prevent exaggerated CsA accumulation in Mrp2⁻/⁻ kidneys.
authors.affiliation: Institute of Physiology, University of Greifswald, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Mähler
authors.forename: Martin
authors.initials: M
authors.lastname: Freyer
authors.forename: Rene
authors.initials: R
authors.lastname: Kauschke
authors.forename: Torsten
authors.initials: T
authors.lastname: Schlüter
authors.forename: Antje C
authors.initials: AC
authors.lastname: Steinbach
authors.forename: Stefan
authors.initials: S
authors.lastname: Oswald
authors.forename: Bärbel
authors.initials: B
authors.lastname: Miehe
authors.forename: Alexander
authors.initials: A
authors.lastname: Krebs
authors.forename: Rainer
authors.initials: R
authors.lastname: Rettig
authors.forename: Olaf
authors.initials: O
authors.lastname: Grisk
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000009:adverse effects* / Q000097:blood; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005919:Glomerular Filtration Rate / Q000187:drug effects; D019803:Glutathione Disulfide / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013481:Superoxides / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D013481:Superoxides; D016572:Cyclosporine; C095122:multidrug resistance protein 3; D019803:Glutathione Disulfide