PF-06869206 is selective inhibitor of renal Pi transport: Evidence from in vitro and in vivo studies.

PF-06869206 is selective inhibitor of renal Pi transport: Evidence from in vitro and in vivo studies. Am J Physiol Renal Physiol. 2020 Aug 03;: Authors: Thomas L, Xue J, Tomilin VN, Pochynyuk OM, Dominguez Rieg JA, Rieg T Abstract Plasma phosphate (Pi) levels are tightly controlled, and elevated plasma Pi levels are associated with an increased risk of cardiovascular complications and death. Two renal transport proteins mediate the majority of Pi reabsorption, the Na+-phosphate cotransporters Npt2a and Npt2c, with Npt2a accounting for 70-80% of Pi reabsorption. The aim of this study was to determine the in vitro effects of a novel Npt2a inhibitor (Npt2a-I, PF-06869206) in opossum kidney (OK) cells as well as determine its selectivity in vivo in Npt2a knockout (Npt2a-/-) mice. In OK cells, Npt2a-I caused dose-dependent reductions of Na+-dependent Pi uptake (IC50: ~1.4 μmol/L), while the unselective Npt2 inhibitor phosphonoformic acid (PFA) resulted in a ~20% stronger inhibition of Pi uptake. The dose-dependent inhibitory effects were present after 24-hour incubation with both low and high Pi media. Michaelis-Menten kinetics in OK cells identified a ~2.4-fold higher Km for Pi in response to Npt2a inhibition with no significant change in apparent Vmax. Higher PTH concentrations decreased Pi uptake equivalent to the maximal inhibitory effect of Npt2a-I. In vivo, the Npt2a-I induced a dose-dependent increase in urinary Pi excretion in wi...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research