MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice.
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.
Kimura
Akihiko
A
Department of Forensic Medicine, Wakayama Medical University, Kimiidera, 641-8509 Wakayama, Japan.
Ishida
Yuko
Y
Wada
Takashi
T
Yokoyama
Hitoshi
H
Mukaida
Naofumi
N
Kondo
Toshikazu
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000032:analysis / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001151:Arsenic; D005978:Glutathione; D008668:Metallothionein; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016601:RNA-Binding Proteins; C436043:Zfand2a protein, mouse; C421109:multidrug resistance-associated protein 1