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Am J Physiol Renal Physiol 280: F636-F645, 2001;
0363-6127/01 $5.00
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Vol. 280, Issue 4, F636-F645, April 2001

Two apical multidrug transporters, P-gp and MRP2, are differently altered in chronic renal failure

Denise Laouari1, Ruchun Yang1, Celine Veau2, Isabelle Blanke1, and Gérard Friedlander1

1 Institut National de la Santé et de la Recherche MédicaleU-426 and Institut Federatif de Recherche "Cellules Epithéliales," Faculté Xavier Bichat, 75018 Paris; and 2 Unité Propre de Recherche et Enseignement Superieur 2706, Faculté de Pharmacie, 92290 Chatenay-Malabry, France

Tubular function is altered in chronic renal failure (CRF). Whether drug secretion by renal tubules is modified in CRF is questioned because of frequent accumulation of various toxins in CRF. This function mainly involves ATP-dependent drug transporters, particularly P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2, both present in apical membrane of epithelial cells. The present study was aimed at determining the changes in P-gp and MRP2 expression induced by experimental CRF in kidney and liver. The relationship between MRP2 and glutathione metabolism changes was examined because MRP2 transports GSSG and glutathione conjugates. Rats underwent either 80% subtotal nephrectomy (Nx) or sham operation, and determinations were performed 3 and 6 wk later. CRF induced a 70-200% rise in protein and mRNA expression of MRP2 after 3 and 6 wk post-Nx in remnant kidney and after 6 wk in liver. However, P-gp expression was unchanged by CRF. Relative to whole kidney mass, total MRP2 levels decreased by only 27% in Nx rats whereas total P-gp levels were reduced by 60%. Renal GSSG and total glutathione levels were increased by 30% in Nx rats, but glutathione-S-transferase (GST) activity was normal; liver GSSG levels and GST activity were reduced in Nx rats. In conclusion, CRF resulted in specific overexpression of MRP2 in kidney and liver. This could be an adaptative response to some elevated circulating toxins. The later MRP2 induction and different glutathione changes in liver compared with kidney suggest different mechanisms for MRP2 induction and/or action in these two tissues.

tubular function; uremia; rat; drug excretion; P-glycoprotein; multidrug resistance-associated protein 2


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