Seventy-five percent nephrectomy and the disposition of inorganic mercury in 2,3-dimercaptopropanesulfonic acid-treated rats lacking functional multidrug-resistance protein 2

Abstract

In the present study, we evaluated the disposition of inorganic mercury (Hg(2+)) in sham-operated and 75% nephrectomized (NPX) Wistar and transport-deficient (TR(-)) rats treated with saline or the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Based on previous studies, DMSA and TR(-) rats were used as tools to examine the potential role of multidrug-resistance protein 2 (MRP2) in the disposition of Hg(2+) during renal insufficiency. All animals were treated with a low dose (0.5 mumol/kg i.v.) of mercuric chloride (HgCl(2)). At 24 and 28 h after exposure to HgCl(2), matched groups of Wistar and TR(-) rats received normal saline or DMSA (intraperitoneally). Forty-eight hours after exposure to HgCl(2), the disposition of Hg(2+) was examined. A particularly notable effect of 75% nephrectomy in both strains of rats was enhanced renal accumulation of Hg(2+), specifically in the outer stripe of the outer medulla. In addition, hepatic accumulation, fecal excretion, and blood levels of Hg(2+) were enhanced in rats after 75% nephrectomy, especially in the TR(-) rats. Treatment with DMSA increased both the renal tubular elimination and urinary excretion of Hg(2+) in all rats. DMSA did not, however, affect hepatic content of Hg(2+), even in the 75% NPX TR(-) rats. We also show with real-time polymerase chain reaction that after 75% nephrectomy and compensatory renal growth, expression of MRP2 (only in Wistar rats) and organic anion transporter 1 is enhanced in the remaining functional proximal tubules. We conclude that MRP2 plays a significant role in the renal and corporal disposition of Hg(2+) after a 75% reduction of renal mass.

Fig. 1.

Results from real-time PCR analyses of the expression of Mrp2 and Oat1 in samples of combined renal cortex and outer stripe of the outer medulla from SO and 75% NPX Wistar and TR⁻ rats 14 days after surgery. ∗ indicates significantly different (p < 0.05) from corresponding control. + indicates significantly different (p < 0.05) from the corresponding mean obtained from Wistar rats.

Fig. 2.

Renal concentration of Hg²⁺ in SO and 75% NPX Wistar and TR⁻ rats, treated with an intraperitoneal 100 mg/kg dose of DMSA or saline 24 and 28 h after being injected intravenously with a 0.5 μmol/kg dose of mercuric chloride. Animals were sacrificed 48 h after being injected with Hg²⁺. Each value represents the mean ± S.E. from four animals. ∗ indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with saline. X indicates significantly different (p < 0.05) from the corresponding group of TR⁻ rats treated with saline. # indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with DMSA. + indicates significantly different (p < 0.05) from the corresponding group of SO rats treated in the same manner.

Fig. 3.

Concentration of Hg²⁺ in the renal cortex of SO and 75% NPX Wistar and TR⁻ rats, treated with an intraperitoneal 100 mg/kg dose of DMSA or saline 24 and 28 h after being injected intravenously with a 0.5 μmol/kg dose of mercuric chloride. Animals were sacrificed 48 h after being injected with Hg²⁺. Each value represents the mean ± S.E. from four animals. ∗ indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with saline. X indicates significantly different (p < 0.05) from the corresponding group of TR⁻ rats treated with saline. # indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with DMSA. + indicates significantly different (p < 0.05) from the corresponding group of SO rats treated in the same manner.

Fig. 4.

Concentration of Hg²⁺ in the renal outer stripe of the outer medulla of SO and 75% NPX Wistar and TR⁻ rats, treated with an intraperitoneal 100 mg/kg dose of DMSA or saline 24 and 28 h after being injected intravenously with a 0.5 μmol/kg dose of mercuric chloride. Animals were sacrificed 48 h after being injected with Hg²⁺. Each value represents the mean ± S.E. from four animals. ∗ indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with saline. X indicates significantly different (p < 0.05) from the corresponding group of TR⁻ rats treated with saline. # indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with DMSA. + indicates significantly different (p < 0.05) from the corresponding group of SO rats treated in the same manner.

Fig. 5.

Amount of Hg²⁺ excreted in the urine in 24 h by SO and 75% NPX Wistar and TR⁻ rats treated with an intraperitoneal 100 mg/kg dose of DMSA or saline 24 and 28 h after being injected intravenously with a 0.5 μmol/kg dose of mercuric chloride. Animals were sacrificed 48 h after being injected with Hg²⁺. Each value represents the mean ± S.E. from four animals. ∗ indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with saline. X indicates significantly different (p < 0.05) from the corresponding group of TR⁻ rats treated with saline. # indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with DMSA. + indicates significantly different (p < 0.05) from the corresponding group of SO rats treated in the same manner.

Fig. 6.

Hepatic content of Hg²⁺ in SO and 75% NPX Wistar and TR⁻ rats treated with an intraperitoneal 100 mg/kg dose of DMSA or saline 24 and 28 h after being injected intravenously with a 0.5 μmol/kg dose of mercuric chloride. Animals were sacrificed 48 h after being injected with Hg²⁺. Each value represents the mean ± S.E. from four animals. ∗ indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with saline. # indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with DMSA. + indicates significantly different (p < 0.05) from the corresponding group of SO rats treated in the same manner.

Fig. 7.

Amount of Hg²⁺ excreted in the feces in 24 h by SO and 75% NPX Wistar and TR⁻ rats treated with an intraperitoneal 100 mg/kg dose of DMSA or saline 24 and 28 h after being injected intravenously with a 0.5 μmol/kg dose of mercuric chloride. Animals were sacrificed 48 h after being injected with Hg²⁺. Each value represents the mean ± S.E. from four animals. ∗ indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with saline. # indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with DMSA. + indicates significantly different (p < 0.05) from the corresponding group of SO rats treated in the same manner.

Fig. 8.

Estimated content of Hg²⁺ in the total blood volume of SO and 75% NPX Wistar and TR⁻ rats treated with an intraperitoneal 100 mg/kg dose of DMSA or saline 24 and 28 h after being injected intravenously with a 0.5 μmol/kg dose of mercuric chloride. Animals were sacrificed 48 h after being injected with Hg²⁺. Blood volume was estimated to be 6% of body weight. Each value represents the mean ± S.E. from four animals. ∗ indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with saline. # indicates significantly different (p < 0.05) from the corresponding group of Wistar rats treated with DMSA. + indicates significantly different (p < 0.05) from the corresponding group of SO rats treated in the same manner.