Document Detail

Secretion of platelet-activating factor is mediated by MDR1 P-glycoprotein in cultured human mesangial cells.
MedLine Citation:
PMID:  10541289     Owner:  NLM     Status:  MEDLINE    
MDR1 P-glycoprotein (Pgp), the product of the MDR1 gene involved in multidrug resistance in cancer cells, is also expressed in normal tissues. In the human kidney, it is localized in the mesangium, the proximal tubule, the thick ascending limb of Henle's loop, and the collecting duct. Pgp actively transports lipophilic xenobiotics, peptides, steroids, and lipids, and perhaps endogenous substrates. It has been shown previously that human mesangial cells in culture express active Pgp and that the expression of Pgp can be down-regulated by exposure to antisense oligonucleotides. Mesangial cells do not express multidrug resistance-related protein (MRP). Experiments were performed to determine whether 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (generically platelet-activating factor, PAF) is a substrate of Pgp in human mesangial cells in culture. This study found: (1) PAF C-16 and analogs inhibited Pgp-mediated efflux of rhodamine 123 by 59 to 88% in multidrug-resistant KBV-1 cells and by 85 to 97% in cultured human mesangial cells. (2) In mesangial cells stimulated with A23187, the secretion of endogenously produced PAF was inhibited by >80% by the Pgp blockers verapamil, cyclosporin A, PSC-833, vinblastine, and adriamycin. (3) Preincubation with MDR1 antisense oligonucleotides also blocked PAF secretion by human mesangial cells. PAF analogs do not modify the transport of MRP substrates in MCF-7/VP cells expressing MRP but not Pgp. These results indicate that PAF is an endogenous substrate of Pgp in human mesangial cells. Inhibition of Pgp transport may be useful in reducing glomerular damage occurring in pathologic conditions where PAF secretion is elevated.
S Ernest; E Bello-Reuss
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  10     ISSN:  1046-6673     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  1999 Nov 
Date Detail:
Created Date:  1999-11-18     Completed Date:  1999-11-18     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2306-13     Citation Subset:  IM    
Department of Internal Medicine, The University of Texas Medical Branch, Galveston 77555-0562, USA.
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MeSH Terms
Biological Transport
Cells, Cultured
Cyclosporine / pharmacology
Glomerular Mesangium / cytology,  drug effects,  secretion*
P-Glycoprotein / physiology*
Platelet Activating Factor / pharmacology,  secretion*
Rhodamine 123 / pharmacokinetics
Grant Support
Reg. No./Substance:
0/P-Glycoprotein; 0/Platelet Activating Factor; 59865-13-3/Cyclosporine; 62669-70-9/Rhodamine 123

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