engleski

The expression of multidrug resistance P-glycoprotein (mdr1) increases along kidney proximal tubule segments (S1-S3), and its distribution inverses in cadmium-intoxicated rats

THE EXPRESSION OF MULTIDRUG RESISTANCE P-GLYCOPROTEIN (mdr1) INCREASES ALONG THE KIDNEY PROXIMAL TUBULE SEGMENTS (S1-S3), AND ITS DISTRIBUTION INVERSES IN CADMIUM-INTOXICATED RATS. F. Thevenod, C. Heark-Kramberger & I. Sabolic. Mdr1 is an ATP-dependent transporter expressed in the kidney proximal tubule (PT) apical membrane, where it may contribute to the excretion of toxic organic compounds. It has been suggested that mdr1 expression is upregulated by heat shock and nephrotoxic heavy metal ions (K.-V. Chin et al., J. Biol. Chem. 265:221-226, 1990). In this study, we have investigated the distribution of mdr1 protein along the nephron in control and cadmium (Cd)-intoxicated rats. Cd-intoxication was induced by injecting CdCl2 (2 mg Cd/kg b.w.), s.c., daily for up to 14 days. Control animals were given saline. Mdr1 expression in renal tissue was determined with the anti-mdr1 monoclonal antibody C219 by indirect immunofluorescence in frozen sections of kidney tissue and by Western blot analysis of proteins in brush-border membranes (BBM) isolated from superficial cortex (SC) and outer stripe (OS). In control animals, the immunofluorescence staining with C219 of brush-border in proximal convoluted tubules (PCT) was weak, whereas the staining of brush-border in proximal straight tubules (PST) was strong. Western blot analysis of proteins in BBM from OS revealed a 2-fold higher amount of the 170 kDa mdr1 protein compared to that in BBM from SC. Following daily Cd injections, the amount of mdr1 protein in BBM from SC changed little during the first 8-10 days, but increased significantly after 12-14 days of treatment. In BBM from OS, however, after 10-14 days of Cd-treatment we observed a 3-4-fold decrease in the amount of mdr1. In agreement with the Western blot data, immunofluorescence histochemistry showed an increased staining of brush-border in PCT with C219, whereas the staining of brush-border in PST was strongly reduced. The data show that a) expression of the mdr1 protein in BBM along the segments (S1-S3) of PT in control rats follows the sequence S1<S2<S3, and b) in nephrotoxicity induced by Cd, the expression of mdr1 in the S1 and S2 PT segments is upregulated, whereas it is downregulated in the S3 segment, thus indicating the presence of different control mechanisms of mdr1 expression in the initial (S1 and S2) and terminal (S3) segments of the PT. II. Physiologisches Institut, Universitat des Saarlandes, Medizinische Fakultat, D-66421 Homburg/Saar and IMI, Zagreb, Croatia.

multidrug resistance;P-glycoprotein; proximal tubule; cadmium; nephropathy; rat

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