title: Sphingolipid signaling reduces basal P-glycoprotein activity in renal proximal tubule.
abstract: P-glycoprotein is an ATP-driven xenobiotic export pump that is highly expressed in barrier and excretory tissues, where it greatly influences drug pharmacokinetics. Recent studies in the blood-brain and spinal cord barriers identified a sphingolipid-based signaling pathway that regulates basal activity of P-glycoprotein. Here we use an established comparative renal model that permits direct measurement of P-glycoprotein activity to determine whether such signaling occurs in another tissue, killifish renal proximal tubule. Isolated killifish tubules exposed to 0.01-1.0 μM sphingosine-1-phosphate (S1P) exhibited a profound decrease in P-glycoprotein transport activity, measured as specific accumulation of a fluorescent cyclosporine A derivative in the tubule lumen. Loss of activity had a rapid onset and was fully reversible when the S1P was removed. Transport mediated by multidrug resistance-associated protein 2 (Mrp2) or a teleost fish organic anion transporter (Oat) was not affected. S1P effects were blocked by a specific S1P receptor 1 (S1PR1) antagonist and mimicked by a S1PR agonist. Sphingosine also reduced P-glycoprotein transport activity and those effects were blocked by an inhibitor of sphingosine kinase and by the S1PR1 antagonist. These results for a comparative renal model suggest that sphingolipid signaling to P-glycoprotein is not just restricted to the blood-brain and blood-spinal cord barriers, but occurs in other excretory and barrier tissues.
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and Mount Desert Island Biological Laboratory, Salsbury Cove, Maine.
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D023781:Fundulidae; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D013110:Sphingosine