QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.089094v1 315/2/912    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Notenboom, S. Articles by Masereeuw, R. Search for Related Content PubMed PubMed Citation Articles by Notenboom, S. Articles by Masereeuw, R.

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Short-Term Exposure of Renal Proximal Tubules to Gentamicin Increases Long-Term Multidrug Resistance Protein 2 (Abcc2) Transport Function and Reduces Nephrotoxicant Sensitivity

Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands (S.N., L.H.K., P.S., F.G.M.R., R.M.); Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (D.S.M.); and Mount Desert Island Biological Laboratory, Salisbury Cove, Maine (S.N., D.S.M., L.H.K.)

We previously showed that the function of renal multidrug resistance protein (Mrp) 2 (Abcc2) is reduced by endothelin (ET)-1 signaling through an ET_B receptor, nitric-oxide synthase (NOS), cGMP, and protein kinase C and that this pathway was activated by several nephrotoxicants (Masereeuw et al., 2000; Terlouw et al., 2001; Notenboom et al., 2002, 2004). Here, we determined the long-term effects on Mrp2-mediated transport (luminal fluorescein methotrexate accumulation) of short-term (30 min) exposure to ET-1 and the aminoglycoside antibiotic, gentamicin. Our data show that over the 3 h following exposure, proximal tubules recovered fully from the initial decrease in Mrp2-mediated transport and that transport activity was not changed 9 h later. However, 24 h after exposure, luminal accumulation of an Mrp2 substrate had increased by 50%. Increased transport at 24 h was accompanied by an increased transporter protein content of the luminal plasma membrane as measured by immunostaining. Blocking ET-1 signaling at the ET_B receptor or downstream at NOS or guanylyl cyclase abolished both stimulation of transport and increased transporter expression. Thus, regardless of whether signaling was initiated by a short exposure to ET-1 or to a nephrotoxicant, the time course of Mrp2 response to ET_B signaling was the same and was multiphasic. Finally, when tubules were exposed to gentamicin for 30 min and removed to gentamicin-free medium for 24 h, they were less sensitive to acute gentamicin toxicity than paired controls not initially exposed to the drug. Thus, short-term exposure to ET-1 or gentamicin resulted in long-term protection against a second insult.

Address correspondence to: Dr. Rosalinde Masereeuw, Department of Pharmacology and Toxicology, 233 Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: r.masereeuw{at}ncmls.ru.nl

This article has been cited by other articles:

				V. Reichel, R. Masereeuw, J. J. M. W. van den Heuvel, D. S. Miller, and G. Fricker Transport of a fluorescent cAMP analog in teleost proximal tubules Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2007; 293(6): R2382 - R2389. [Abstract] [Full Text] [PDF]

				D. S. Miller, J. R. Shaw, C. R. Stanton, R. Barnaby, K. H. Karlson, J. W. Hamilton, and B. A. Stanton MRP2 and Acquired Tolerance to Inorganic Arsenic in the Kidney of Killifish (Fundulus heteroclitus) Toxicol. Sci., May 1, 2007; 97(1): 103 - 110. [Abstract] [Full Text] [PDF]

				K. E. Wever, R. Masereeuw, D. S. Miller, X. M. Hang, and G. Flik Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport Am J Physiol Renal Physiol, January 1, 2007; 292(1): F38 - F46. [Abstract] [Full Text] [PDF]

				S. Notenboom, A. C. Wouterse, B. Peters, L. H. Kuik, S. Heemskerk, F. G. M. Russel, and R. Masereeuw Increased Apical Insertion of the Multidrug Resistance Protein 2 (MRP2/ABCC2) in Renal Proximal Tubules following Gentamicin Exposure J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1194 - 1202. [Abstract] [Full Text] [PDF]