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Plasma phosphate (P i ) levels are tightly controlled, and elevated plasma P i levels are associated with an increased risk of cardiovascular complications and death. Two renal transport proteins mediate the majority of P i reabsorption: Na + -phosphate cotransporters Npt2a and Npt2c, with Npt2a accounting for 70–80% of P i reabsorption. The aim of the present study was to determine the in vitro effects of a novel Npt2a inhibitor (PF-06869206) in opossum kidney (OK) cells as well as determine its selectivity in vivo in Npt2a knockout (Npt2a −/− ) mice. In OK cells, Npt2a inhibitor caused dose-dependent reductions of Na + -dependent P i uptake (IC 50 : ~1.4 μmol/L), whereas the unselective Npt2 inhibitor phosphonoformic acid (PFA) resulted in an ~20% stronger inhibition of P i uptake. The dose-dependent inhibitory effects were present after 24 h of incubation with both low- and high-P i media. Michaelis-Menten kinetics in OK cells identified an ~2.4-fold higher K m for P i in response to Npt2a inhibition with no significant change in apparent V max . Higher parathyroid hormone concentrations decreased P i uptake equivalent to the maximal inhibitory effect of Npt2a inhibitor. In vivo, the Npt2a inhibitor induced a dose-dependent increase in urinary P i excretion in wild-type mice (ED 50 : ~23 mg/kg), which was completely absent in Npt2a −/− mice, alongside a lack of decrease in plasma P i . Of note, the Npt2a inhibitor-induced dose-dependent increase in urinary Na + excretion was still present in Npt2a −/− mice, a response possibly mediated by an off-target acute inhibitory effect of the Npt2a inhibitor on open probability of the epithelial Na + channel in the cortical collecting duct.

PF-06869206 is a selective inhibitor of renal Pitransport: evidence from in vitro and in vivo studies

PF-06869206 is a selective inhibitor of renal P_itransport: evidence from in vitro and in vivo studies