Abstract:
:Hyperphosphatemia is associated with severe decline of renal function in chronic kidney disease and elevates cardiovascular mortality. Type II sodium dependent phosphate transporter 2A (Npt2A) plays a major role in renal phosphate reabsorption and could be explored as a target for anti-hyperphosphatemia therapy. Human Npt2A transporter activity was examined upon transfection into CHO, MDCK, HEK293, Flp-In-CHO and Flp-In-HEK293 cells. Only kidney-derived cells expressed functional Npt2A. HEK293 and Flp-In-HEK293 cell lines stably transfected with hNpt2A could be selected, but these cells were inactive in phosphate transport. This suggests that high-level, constitutive Npt2A expression has deleterious effects on the cell. By using the conditional promoter in the Flp-In-Trex vector, functional expression of Npt2A was achieved by doxycycline induction in HEK293 cells. The EGFP tagged and non-tagged, inducible stable hNpt2A-HEK293 cell lines afforded development of a robust phosphate uptake assay mediated by hNpt2A, which can be used to screen hNpt2A inhibitors and inducers of hNpt2A expression. Using this assay, the small molecule LC-1 was identified as a potent inhibitor of hNpt2A, suggesting that it is feasible to develop potent specific hNpt2A inhibitors to control phosphate overloading for hyperphosphatemia therapy.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Wu H,Mao C,Duenstl G,Su W,Qian Sdoi
10.1016/j.ejphar.2013.09.005subject
Has Abstractpub_date
2013-12-05 00:00:00pages
332-40issue
1-3eissn
0014-2999issn
1879-0712pii
S0014-2999(13)00655-9journal_volume
721pub_type
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