Xenobiotic export pumps, endothelin signaling, and tubular nephrotoxicants--a case of molecular hijacking.
This article is a review on recent studies in intact renal proximal tubules that link tubular nephrotoxicants with endothelin (ET) regulation of xenobiotic export pump function. The data show that transport on p-glycoprotein and Mrp2 decreases rapidly when ET signals through an ET(B) receptor, NO synthase (NOS), and protein kinase C (PKC). Surprisingly, nephrotoxicants, such as radiocontrast agents, aminoglycoside antibiotics, and heavy metal salts, "hijack" this signaling pathway, causing ET release from the tubules, hormone binding to its receptor, activation of NOS and PKC, and reduced xenobiotic transport. These findings suggest a new common mechanism by which nephrotoxicants may act to disrupt renal tubular function.
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. miller@niehs.nih.gov
David S
DS
Miller
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D005452:Fluoresceins / Q000633:toxicity*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D007695:Killifishes; D026901:Membrane Transport Proteins; D008727:Methotrexate / Q000031:analogs & derivatives / Q000633:toxicity*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D015262:Xenobiotics / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002118:Calcium; D016232:Endothelins; D005452:Fluoresceins; D026901:Membrane Transport Proteins; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009569:Nitric Oxide; D011493:Protein Kinase C; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D015262:Xenobiotics; C421109:multidrug resistance-associated protein 1