title: Nitric oxide down-regulates the expression of organic cation transporters (OCT) 1 and 2 in rat kidney during endotoxemia.
abstract: In the kidney, P-glycoprotein (Abcb1), an ATP-driven drug efflux pump, plays an important role in the detoxification of proximal tubule cells through the excretion of cationic and amphipathic organic compounds. We recently found that NO, produced by renal inducible NO synthase (iNOS), is involved in an up-regulation of P-glycoprotein during endotoxemia in rats. In the present study, we investigated the functional consequences of endotoxemia on the renal handling of rhodamine 123 by using isolated perfused rat kidneys. Wistar Hannover rats were injected intraperitoneally with 5 mg/kg body weight lipopolysaccharide (LPS) or with both LPS and the iNOS inhibitor, aminoguanidine. Despite an increased P-glycoprotein expression, we found a diminished urinary rhodamine 123 clearance 12 h after LPS (P<0.001). In addition, we found a diminished perfusate clearance (P<0.05) for rhodamine 123 after LPS treatment, suggesting a predominant role of influx carriers in urinary rhodamine 123 excretion. We examined the expression levels of organic cation transporter 1 (Slc22a1/Oct1) and Slc22a2/Oct2. Both appeared to be down-regulated at the mRNA and protein level, 12 h after LPS. Co-administration of aminoguanidine attenuated the down-regulation of both Oct1 and Oct2 protein expression and reversed the decrease in rhodamine 123 clearance (P<0.001). These findings indicate that NO, produced by iNOS, is responsible for a down-regulation of the influx carriers, Oct1 and Oct2.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Heemskerk
authors.forename: Alfons C
authors.initials: AC
authors.lastname: Wouterse
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000652:urine; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D050482:Catecholamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D006146:Guanidines; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger; C493212:Slc22a1 protein, rat; C100590:Slc22a2 protein, rat; D020112:Rhodamine 123; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine