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Secretion of platelet-activating factor is mediated by MDR1 P-glycoprotein in cultured human mesangial cells
1Department of Internal Medicine, The University of Texas Medical Branch, Galveston 77555-0562, USA.
Abstract:
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.
Insights
Platelet-activating factor (PAF) is an endogenous substrate of P-glycoprotein (Pgp) in human kidney mesangial cells. Inhibiting Pgp may reduce glomerular damage linked to elevated PAF secretion in certain diseases.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- P-glycoprotein (Pgp), encoded by the MDR1 gene, confers multidrug resistance and is present in normal human kidney tissues.
- Pgp is expressed in human mesangial cells and actively transports various substances, but its role with endogenous molecules like PAF was unclear.
- Human mesangial cells express Pgp but not multidrug resistance-related protein (MRP).
Purpose of the Study:
- To investigate if platelet-activating factor (PAF) is an endogenous substrate of P-glycoprotein (Pgp) in cultured human mesangial cells.
- To assess the potential therapeutic implications of inhibiting Pgp in conditions involving elevated PAF secretion.
Main Methods:
- Assessing the effect of PAF analogs on Pgp-mediated rhodamine 123 efflux in multidrug-resistant cells and human mesangial cells.
- Measuring the inhibition of endogenously produced PAF secretion in stimulated mesangial cells using Pgp blockers.
- Evaluating the impact of MDR1 antisense oligonucleotides on PAF secretion and testing PAF analog effects on MRP substrates.
Main Results:
- PAF analogs significantly inhibited Pgp-mediated efflux of rhodamine 123 in both KBV-1 cells and human mesangial cells.
- Pgp blockers (verapamil, cyclosporin A, etc.) and MDR1 antisense oligonucleotides markedly reduced PAF secretion in mesangial cells.
- PAF analogs did not affect MRP substrate transport, confirming Pgp specificity.
Conclusions:
- Platelet-activating factor (PAF) is identified as an endogenous substrate of P-glycoprotein (Pgp) in human mesangial cells.
- The findings suggest that inhibiting Pgp activity could be a therapeutic strategy to mitigate glomerular damage in pathological conditions characterized by increased PAF secretion.
