Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice.
Expressed in liver, aquaglyceroporin-9 (AQP9) is permeated by glycerol, arsenite, and other small, neutral solutes. To evaluate a possible protective role, AQP9-null mice were evaluated for in vivo arsenic toxicity. After injection with NaAsO(2), AQP9-null mice suffer reduced survival rates (LD(50), 12 mg/kg) compared with WT mice (LD(50), 15 mg/kg). The highest tissue level of arsenic is in heart, with AQP9-null mice accumulating 10-20 times more arsenic than WT mice. Within hours after NaAsO(2) injection, AQP9-null mice sustain profound bradycardia, despite normal serum electrolytes. Increased arsenic levels are also present in liver, lung, spleen, and testis of AQP9-null mice. Arsenic levels in the feces and urine of AQP9-null mice are only approximately 10% of the WT levels, and reduced clearance of multiple arsenic species by the AQP9-null mice suggests that AQP9 is involved in the export of multiple forms of arsenic. Immunohistochemical staining of liver sections revealed that AQP9 is most abundant in basolateral membrane of hepatocytes adjacent to the sinusoids. AQP9 is not detected in heart or kidney by PCR or immunohistochemistry. We propose that AQP9 provides a route for excretion of arsenic by the liver, thereby providing partial protection of the whole animal from arsenic toxicity.
Carbrey
Jennifer M
JM
Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA. jennifer.carbrey@duke.edu
Song
Linhua
L
Zhou
Yao
Y
Yoshinaga
Masafumi
M
Rojek
Aleksandra
A
Wang
Yiding
Y
Liu
Yangjian
Y
Lujan
Heidi L
HL
DiCarlo
Stephen E
SE
Nielsen
Søren
S
Rosen
Barry P
BP
Agre
Peter
P
Mukhopadhyay
Rita
R
D000818:Animals; D020346:Aquaporins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001151:Arsenic / Q000493:pharmacokinetics* / Q000633:toxicity*; D018053:Arsenites / Q000493:pharmacokinetics / Q000633:toxicity; D004562:Electrocardiography; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D007150:Immunohistochemistry; D007928:Lethal Dose 50; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D017670:Sodium Compounds / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution
C491638:Aqp9 protein, mouse; D020346:Aquaporins; D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite; D001151:Arsenic