Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule.
In the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-tubular lumen transport of both fluorescent compounds. These effects were prevented by an ET(B) receptor antagonist but not by an ET(A) receptor antagonist. Immunostaining with an antibody to mammalian ET(B) receptors showed specific localization to the basolateral membrane of the fish tubular epithelial cells. ET-1 effects on transport were blocked by protein kinase C-selective inhibitors, implicating protein kinase C in ET-1 signaling. Finally, the nephrotoxic radiocontrast agent iohexol reduced cell-to-lumen FL-MTX and NBD-CSA transport, and these effects were abolished by an ET(B) receptor antagonist. These are the first results linking ET to the control of xenobiotic transport and the first demonstrating control of renal multidrug resistance-associated protein 2 and P-glycoprotein by a hormone.
Masereeuw
R
R
Department of Pharmacology, University of Nijmegen, Nijmegen, The Netherlands. R.Masereeuw@farm.kun.nl
Terlouw
S A
SA
van Aubel
R A
RA
Russel
F G
FG
Miller
D S
DS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D027321:Anion Transport Proteins; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics*; D016232:Endothelins / Q000378:metabolism; D005452:Fluoresceins / Q000493:pharmacokinetics*; D007472:Iohexol / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D007695:Killifishes; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011493:Protein Kinase C / Q000378:metabolism; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*
C091682:(N-5-(4-nitrobenzofurazan-7-yl)lysyl(8))cyclosporine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027321:Anion Transport Proteins; D002352:Carrier Proteins; D016232:Endothelins; D005452:Fluoresceins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C103864:fluorescein-methotrexate; D007472:Iohexol; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D008727:Methotrexate