MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice.

Abstract

To clarify the pathophysiological mechanism underlying acute renal injury caused by acute exposure to arsenic, we subcutaneously injected both BALB/c and C57BL/6 mice with sodium arsenite (NaAs; 13.5 mg/kg). BALB/c mice exhibited exaggerated elevation of serum blood urea nitrogen (BUN) and creatinine (CRE) levels, compared with C57BL/6 mice. Moreover, half of BALB/c mice died by 24 h, whereas all C57BL/6 mice survived. Histopathological examination on kidney revealed severe hemorrhages, acute tubular necrosis, neutrophil infiltration, cast formation, and disappearance of PAS-positive brush borders in BALB/c mice, later than 10 h. These pathological changes were remarkably attenuated in C57BL/6 mice, accompanied with lower intrarenal arsenic concentrations, compared with BALB/c mice. Among heavy metal inducible proteins including multidrug resistance-associated protein (MRP)-1, multidrug resistance gene (MDR)-1, metallothionein (MT)-1, and arsenite inducible, cysteine- and histidine-rich RNA-associated protein (AIRAP), intrarenal MDR-1, MT-1, and AIRAP gene expression was enhanced to a similar extent in both strains, whereas NaAs challenge augmented intrarenal MRP-1 mRNA and protein expression levels in C57BL/6 but not BALB/c mice. Moreover, the administration of a specific inhibitor of MRP-1, MK-571, significantly exaggerated acute renal injury in C57BL/6 mice. Thus, MRP-1 is crucially involved in arsenic efflux and eventually prevention of acute renal injury upon acute exposure to NaAs.

• Authors: Akihiko Kimura, Yuko Ishida, Takashi Wada, Hitoshi Yokoyama, Naofumi Mukaida, Toshikazu Kondo
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 203 Issue 1 Pg. 53-61 (Feb 15 2005) ISSN: 0041-008X [Print] United States
• PMID: 15694464 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Multidrug Resistance-Associated Proteins
• RNA-Binding Proteins
• Zfand2a protein, mouse
• Metallothionein
• Glutathione
• Arsenic
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Animals
• Arsenic (analysis, toxicity)
• Gene Expression Regulation (drug effects)
• Glutathione (metabolism)
• Kidney (drug effects, metabolism, pathology)
• Male
• Metallothionein (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Multidrug Resistance-Associated Proteins (analysis, biosynthesis, genetics)
• RNA-Binding Proteins (genetics, metabolism)
• Species Specificity
• Time Factors