P-glycoprotein inhibitors stimulate renal phosphate reabsorption in rats.
BACKGROUND
Dipyridamole (Dip) was previously shown to increase renal phosphate (Pi) reabsorption in humans. However, the mechanism(s) underlying this renal tubular effect is not fully elucidated. It is known that Dip inhibits the activity of the P-glycoprotein (Pgp) multidrug resistance protein 1 (MDR1) expressed on the apical membrane of renal proximal tubular cells where the Na-Pi cotransporter (NPT2) is also expressed. We hypothesized that Dip could increase renal Pi reabsorption by inhibiting Pgp activity.


METHODS
To test this hypothesis, the effects of Dip, verapamil (Ver), and cyclosporine A (CsA), three unrelated Pgp inhibitors, were studied on the renal Pi reabsorption in rats.


RESULTS
All three drugs decreased the fractional excretion of Pi (FE(Pi)) in a dose-dependent manner within one hour after beginning the drug infusion, without altering the glomerular filtration rate or serum parathyroid hormone concentration. Sodium-dependent Pi uptake but not Na-glucose transport was increased in brush-border membrane vesicles (BBMVs) when comparing treated with untreated rats. Western blot analysis showed that NPT2 protein was increased in BBMVs from treated rats. Dip and Ver had no effect when applied directly to BBMVs prepared from untreated rats. Pretreatment of rats with colchicine prevented the effects of Dip on the FE(Pi) and NPT2 expression in brush-border membranes.


CONCLUSIONS
Our results suggest that inhibition of Pgp in the proximal tubule increases Pi uptake and NPT2 translocation to the apical membrane.
Prié
D
D
INSERM U426 and Department of Physiology, Faculté de Médecine Xavier Bichat, Université Paris 7, France. dprie@bichat.inserm.fr
Couette
S
S
Fernandes
I
I
Silve
C
C
Friedlander
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010710:Phosphates / Q000378:metabolism* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D050608:Sodium-Phosphate Cotransporter Proteins; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters; D015854:Up-Regulation; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D010710:Phosphates; D050608:Sodium-Phosphate Cotransporter Proteins; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D027981:Symporters; D004176:Dipyridamole; D016572:Cyclosporine; D014700:Verapamil; D005947:Glucose