P-glycoprotein inhibitors stimulate renal phosphate reabsorption in rats

Background. Dipyridamole (Dip) was previously shown to increase renal phosp hate (Pi) reabsorption in humans. However, the mechanism(s) underlying this renal tubular effect is not fully elucidated. It is known that Dip inhibit s the activity of the P-glycoprotein (Pgp) multidrug resistance protein I ( MDR1) expressed on the apical membrane of renal proximal tubular cells wher e the Na-Pi cotransporter (NPT2) is also expressed. We hypothesized that Di p 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 r enal Pi reabsorption in rats. Results. All three drugs decreased the fractional excretion of Pi (FEPi) in a dose-dependent manner within one hour after beginning the drug infusion, without altering the glomerular filtration rate or serum parathyroid hormo ne concentration. Sodium-dependent Pi uptake but not Na-glucose transport w as increased in brush-border membrane vesicles (BBMVs) when comparing treat ed with untreated rats. Western blot analysis showed that NPT2 protein was increased in BBMVs from treated rats. Dip and Ver had no effect when applie d directly to BBMVs prepared from untreated rats. Pretreatment of rats with colchicine prevented the effects of Dip on the FEPi and NPT2 expression in brush-border membranes. Conclusions. Our results suggest that inhibition of Pgp in the proximal tub ule increases Pi uptake and NPT2 translocation to the apical membrane.