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Effects of generalized and kidney specific Mrp2 (ABCC2) deficiency on renal elimination of PAH and morphine‐6‐glucuronide
Author(s) -
Grisk Olaf,
Schlüter Torsten,
Steinbach Antje,
Ciecholewski Sabine,
Klöting Ingrid,
Völker Uwe,
Rettig Rainer,
Kroemer Heyo
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a909-a
Subject(s) - multidrug resistance associated protein 2 , kidney , endocrinology , medicine , chemistry , organic anion transporter 1 , biology , transporter , biochemistry , gene , atp binding cassette transporter
To study the role of Mrp2 for renal organic anion elimination without high genetic background variability, Mrp2 deficient congenic Lewis rats (LEW) were bred. RBF, RPF and GFR were similar in Mrp2 deficient and control LEW. With the Mrp2 and Mrp4 substrate PAH infused at 2.8 and 5.6 mg/kg∗h, FE PAH was 6.9 ± 0.3 and 8.4 ± 0.5 in LEW vs. 9.3 ± 0.6 and 11.9 ± 0.5 in Mrp2 deficient LEW (p < 0.001). Western‐blot analysis revealed a fourfold higher renal cortical Mrp4 expression in Mrp2 deficient LEW than in controls. Mrp2 deficient LEW showed a hundredfold reduced biliary morphine‐6‐glucuronide (M6G) elimination indicating that M6G is a Mrp2 substrate. At the plasma concentrations tested, renal M6G elimination was similar in Mrp2 deficient and control LEW with FE M6G close to 1. To investigate kidney specific Mrp2 deficiency, kidneys were cross‐transplanted. FE PAH and FE M6G did not differ between animals with kidney specific Mrp2 deficiency and syngeneically transplanted controls. There was no difference in renal Mrp4 expression between Mrp2 deficient and intact kidney grafts. Renal cortical gene expression profiling revealed 9 more than twofold induced and 4 more than twofold reduced genes in Mrp2 negative grafts transplanted into normal LEW compared to syngeneically transplanted controls. We conclude that generalized but not kidney specific Mrp2 deficiency causes increased FE PAH that is at least in part due to induction of renal Mrp4. Kidney specific Mrp2 deficiency does not compromise renal elimination of PAH and M6G.