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Two renal transport proteins mediate the majority of P<jats:sub>i<\/jats:sub>reabsorption: Na<jats:sup>+<\/jats:sup>-phosphate cotransporters Npt2a and Npt2c, with Npt2a accounting for 70\u201380% of P<jats:sub>i<\/jats:sub>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<jats:sup>\u2212\/\u2212<\/jats:sup>) mice. In OK cells, Npt2a inhibitor caused dose-dependent reductions of Na<jats:sup>+<\/jats:sup>-dependent P<jats:sub>i<\/jats:sub>uptake (IC<jats:sub>50<\/jats:sub>: ~1.4 \u03bcmol\/L), whereas the unselective Npt2 inhibitor phosphonoformic acid (PFA) resulted in an ~20% stronger inhibition of P<jats:sub>i<\/jats:sub>uptake. The dose-dependent inhibitory effects were present after 24 h of incubation with both low- and high-P<jats:sub>i<\/jats:sub>media. Michaelis-Menten kinetics in OK cells identified an ~2.4-fold higher K<jats:sub>m<\/jats:sub>for P<jats:sub>i<\/jats:sub>in response to Npt2a inhibition with no significant change in apparent V<jats:sub>max<\/jats:sub>. Higher parathyroid hormone concentrations decreased P<jats:sub>i<\/jats:sub>uptake equivalent to the maximal inhibitory effect of Npt2a inhibitor. In vivo, the Npt2a inhibitor induced a dose-dependent increase in urinary P<jats:sub>i<\/jats:sub>excretion in wild-type mice (ED<jats:sub>50<\/jats:sub>: ~23 mg\/kg), which was completely absent in Npt2a<jats:sup>\u2212\/\u2212<\/jats:sup>mice, alongside a lack of decrease in plasma P<jats:sub>i<\/jats:sub>. Of note, the Npt2a inhibitor-induced dose-dependent increase in urinary Na<jats:sup>+<\/jats:sup>excretion was still present in Npt2a<jats:sup>\u2212\/\u2212<\/jats:sup>mice, a response possibly mediated by an off-target acute inhibitory effect of the Npt2a inhibitor on open probability of the epithelial Na<jats:sup>+<\/jats:sup>channel in the cortical collecting duct.<\/jats:p>","DOI":"10.1152\/ajprenal.00146.2020","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T09:19:04Z","timestamp":1596446344000},"page":"F541-F551","source":"Crossref","is-referenced-by-count":20,"title":["PF-06869206 is a selective inhibitor of renal P<sub>i<\/sub>transport: evidence from in vitro and in vivo studies"],"prefix":"10.1152","volume":"319","author":[{"given":"Linto","family":"Thomas","sequence":"first","affiliation":[{"name":"Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, 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