engleski

Nephrotoxic heavy metals increase the expression of mdr1 P-glycoprotein in the rat kidney brush-border membrane

The multidrug resistance P-glycoprotein (mdr1) is an 150-170 kDa membrane protein that catalyzes the ATP-dependent efflux of hydrophobic and potentially cytotoxic compounds from the cells and, thus, it may represent an important cellular mechanism of detoxication. In various epithelia, including the kidney proximal tubule (PT), the protein is expressed on the apical cell membrane. An altered expression of mdr1 is commonly seen in tumors treated with chemotherapy or in some cultured cells exposed to environmental stress or cytotoxic heavy metals (1). Using a monoclonal anti-mdr1 antibody (C219), we studied the expression of mdr1 protein in PT cells by indirect immunofluorescence in 4 &#61549;m thick frozen sections of the fixed kidney cortex and by immunoblotting in isolated renal cortical brush-border membranes (BBM) from control rats and from the rats treated in vivo with various heavy metals. Rats were treated with daily s.c. injections of chloride salts of Cd, Hg, Cu, Zn, Mn, Ca, Mg, Al, La (2 mg/kg B.M.) or Pb (5 mg/kg B.M.) for 14 days, or with a single i.p. injection of cis-Pt (5 mg/kg B.M. 5 days before sacrifice). Control rats received an equivalent amount of saline for a comparable time period. A relative amount of mdr1 in BBM was correlated to the metal concentration in the renal cortical tissue measured by atomic absorption spectrometry. In control rats, a very low tissue concentration of the metals was detected and a heterogenous expression of mdr1 in BBM along the PT was found (S1<S2<S3). In metal-treated rats, the concentration of metals in the renal cortical tissue increased between 7-(Mn) and 3000-fold (Cd). In rats treated with Cu, Zn, Mn, Ca, Mg, Al, and La, the abundance of mdr1 in the cortical BBM was not different from that in controls. On the contrary, in rats treated with the well-known nephrotoxic heavy metals, such as cis-Pt, Pb, Cd, and Hg, the mdr1 expression in the cortical BBM increased 3-, 6-, 15-, and 18-fold, respectively. Conclusion: nephrotoxic heavy metals (Cd, Hg, Pb and cis-Pt) increase the expression of mdr1 in the rat kidney cortex BBM in vivo. The increased expression of mdr1 may represent a part of a specific cytoprotective response of the PT cells to oxidative stress induced by nephrotoxic heavy metals. Functioning as a lipid-translocase (2), mdr1 could assist in removal of toxic lipid peroxides generated in the presence of heavy metals by translocating them across the apical membrane into the PT lumen.

multidrug resistance; cadmium; kidney cortex; rat

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