Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia.
Nitric oxide (NO) is an important regulator of renal transport processes. In the present study, we investigated the role of NO, produced by inducible NO synthase (iNOS), in the regulation of renal ATP-binding cassette (ABC) transporters in vivo during endotoxemia. Wistar-Hannover rats were injected with lipopolysaccharide (LPS(+)) alone or in combination with the iNOS inhibitor, aminoguanidine. Controls received detoxified LPS (LPS(-)). After LPS(+), proximal tubular damage and a reduction in renal function were observed. Furthermore, iNOS mRNA and protein, and the amount of NO metabolites in plasma and urine, increased compared to the LPS(-) group. Coadministration with aminoguanidine resulted in an attenuation of iNOS induction and reduction of renal damage. Gene expression of 20 ABC transporters was determined. After LPS(+), a clear up-regulation in Abca1, Abcb1/P-glycoprotein (P-gp), Abcb11/bile salt export pump (Bsep), and Abcc2/multidrug resistance protein (Mrp2) was found, whereas Abcc8 was down-regulated. Up-regulation of Abcc2/Mrp2 was accompanied by enhanced calcein excretion. Aminoguanidine attenuated the effects on transporter expression. Our data indicate that NO, produced locally by renal iNOS, regulates the expression of ABC transporters in vivo. Furthermore, we showed, for the first time, expression and subcellular localization of Abcb11/Bsep in rat kidney.
Heemskerk
Suzanne
S
Department of Pharmacology and Toxicology (149), Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
van Koppen
Arianne
A
van den Broek
Luc
L
Poelen
Geert J M
GJ
Wouterse
Alfons C
AC
Dijkman
Henry B P M
HB
Russel
Frans G M
FG
Masereeuw
Rosalinde
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001806:Blood Urea Nitrogen; D015536:Down-Regulation / Q000187:drug effects; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009589:Nitrogen Oxides / Q000097:blood / Q000652:urine; D030421:Peroxynitrous Acid / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D006146:Guanidines; D008070:Lipopolysaccharides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D009589:Nitrogen Oxides; D030421:Peroxynitrous Acid; C490548:Abcb11 protein, rat; C423013:Abcc2 protein, rat; C489542:Abcc4 protein, rat; C496318:Nos2 protein, rat; C004479:pimagedine; C007740:fluorexon