Deficiency of Multidrug and Toxin Extrusion 1 Enhances Renal Accumulation of Paraquat and Deteriorates Kidney Injury in Mice

Abstract

Multidrug and toxin extrusion 1 (MATE1/solute carrier 47A1) mediates cellular transport of a variety of structurally diverse compounds. Paraquat (PQ), which has been characterized in vitro as a MATE1 substrate, is a widely used herbicide and can cause severe toxicity to humans after exposure. However, the contribution of MATE1 to PQ disposition in vivo has not been determined. In the present study, we generated Mate1-deficient (Mate1–/–) mice and performed toxicokinetic analyses of PQ in Mate1–/– and wild-type (Mate1+/+) mice. After a single intravenous administration of PQ (50 mg/kg), Mate1–/– mice exhibited significantly higher plasma PQ concentrations than Mate1+/+ mice. The renal PQ concentration was markedly increased in Mate1–/– mice compared with Mate1+/+ mice. The subsequent nephrotoxicity of PQ were examined in these mice. Three days after intraperitoneal administration of PQ (20 mg/kg), the transcript levels of N-acetyl-β-d-glucosaminidase (Lcn2) and kidney injury molecule-1 (Kim-1) in the kidney were remarkably enhanced in the Mate1–/– mice. This was accompanied by apparent difference in renal histology between Mate1–/– and Mate1+/+ mice. In conclusion, we demonstrated that Mate1 is responsible for renal elimination of PQ in vivo and the deficiency of Mate1 function confers deteriorated kidney injury caused by PQ in mice.

Xenobiotic transporters and kidney injury

“…The cytotoxicity of PQ in HEK293 cells overexpressing human MATE1 revealed an LC 50 value of 125 μM compared to 717 μM for vector controls [57]. Infusion of 50 mg/kg PQ intravenously in Mate1-deficient mice increased renal PQ concentrations by 147% at 90 min compared to wild-type mice [109]. Additionally, the plasma area-under-the-curve and maximal concentration of PQ in Mate1-null mice were increased 64% and 57%, respectively, compared to wild-type controls.…”

“…Additionally, the plasma area-under-the-curve and maximal concentration of PQ in Mate1-null mice were increased 64% and 57%, respectively, compared to wild-type controls. Mate1-null mice administered PQ (20 mg/kg, intraperitoneally) had significantly higher mRNA levels of two kidney injury biomarkers, N-acetyl-Beta-D-glucosaminidase (NAG) and kidney injury molecule-1 (Kim-1) as well as enhanced necrosis and tubular degeneration compared to wild-type mice [109]. A direct role for MATE2-K still needs to be elucidated.…”

“…Interestingly, Mate1-null mice had reduced accumulation of PQ in their livers which correlated with an induction of liver Mdr1a mRNA expression [109]. However, this compensatory increase was not seen in the kidneys.…”

Multidrug and toxin extrusion proteins mediate cellular transport of cadmium

“…Different from most efflux transporters which belong to the ATP-binding cassette (ABC) transporter family, MATEs use an outward proton gradient as the driving force to transport substrates out of the cell (substrate/H + antiport). Two MATE isoforms are expressed in the apical membrane of human kidney proximal tubules, hMATE1 and hMATE2-K, encoded by SLC47A1 and SLC47A2 genes respectively, while only one isoform (mMate1) is found in mouse kidney which is encoded by Slc47a1 gene (Li et al , 2011). A wide overlap of substrate spectrum has been recognized between OCTs and MATEs (Nies et al , 2011; Yonezawa and Inui, 2011; Muller et al , 2013), which function collaboratively to eliminate their substrates in the kidney.…”

“…Our data have suggested that mouse might be an appropriate in vivo model for this purpose. The genetic mouse models of Mate1 deficiency have been available (Li et al , 2011). With our present in vitro evidence supporting Cd 2+ as a substrate of MATEs, it would be interesting to compare the toxicokinetics and toxicity of Cd 2+ in the mice with different MATE function.…”