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Mechanisms of inhibition of renal phosphate transport by phosphonoformate and arsenate
Author(s) -
VillaBellosta Ricardo,
Levi Moshe,
Sorribas Victor
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a612-b
Subject(s) - arsenate , reabsorption , chemistry , cotransporter , phosphate , parathyroid hormone , ion transporter , pi , biochemistry , transporter , biophysics , membrane , biology , calcium , sodium , arsenic , organic chemistry , gene
Renal reabsorption of inorganic phosphate (Pi) is mediated through the activity of high affinity, type II Na‐coupled Pi cotransporters in the proximal tubular cells. The rate of reabsorption is the main target for hormonal and metabolic factors that control phosphate homeostasis, including parathyroid hormone or adaptation to changes in dietary phosphate. Pi transport is also competitively inhibited by phosphonoformic acid (PFA) and arsenate, with Ki values of 0.13 and 0.2 mM, respectively, in opossum kidney cells (OK; an in vitro model of Pi renal reabsorption). However, NaPi4, the main type II Pi transporter in OK cells, is less efficiently inhibited by PFA and arsenate, with corresponding Ki values of 0.86 and 1 mM. Preincubation of OK cells with 1 mM PFA for 1 hour mimics acute adaptation to low Pi. However, preincubation with 1 mM arsenate has the same effect on transport activity as adaptation to 2 mM Pi. These effects are specific of Pi transport, as no alterations are observed in other Na‐coupled transport processes including Na‐glucose. Time‐course and saturation kinetics suggest that these effects are mediated through changes in the abundance of Pi transporters in the plasma membrane. While both inhibitors act in a competitive manner, only arsenate is efficiently transported and, once inside the cell, it is also recognized as Pi by the sensing mechanisms that induce the cell to adapt to high Pi concentration.