Amelioration of mercury nephrotoxicity after pharmacological manipulation of organic anion transporter 1 (Oat1) and multidrug associated resistance protein 2 (Mrp2) with furosemide

Abstract

Inorganic mercury is a major environmental contaminant. The primary site of mercuryinduced injury is the kidney due to the uptake of Hg(2+) -conjugated organic anions in the proximal tubule, primary across the organic anion transporter 1 (Oat1) at the basolateral membrane. At the luminal side, mercuric ions are eliminated by the multidrug resistanceassociated protein 2 (Mrp2). It was described that furosemide treatment induces up-regulation of Oat1 renal expression. As novel preventive and therapeutic strategies based in pharmacological manipulation of drug transporters are emerging, this study was designed to evaluate the impact of furosemide modulation of Oat1 on the nephrotoxicity induced by HgCl2. Wistar rats were treated with furosemide (6 mg/100 g/ day, s.c.) during 4 days or with HgCl2 (4 mg/kg, i.p.) 18 h before the experiments or with furosemide during 4 days before the HgCl2 injection. Furosemide treatment improved HgCl2-induced tubular injury as assessed by urinary alkaline phosphatase activity, urinary glucose, Oat5 urinary excretion and histopathological studies. Besides, administration of furosemide enhanced mercury urinary excretion, reduced mercury total renal accumulation and increased Mrp2 renal expression. In summary, furosemide improves HgCl2- induced proximal tubule injury up-regulating mercury transporters and thus, increasing renal elimination of the mercuric ions. Hence, pharmacological manipulation of mercury transporters with furosemide might be a preventive strategy to reduce mercury toxicity.