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Uric acid (UA) secretion by avian renal proximal tubule is inhibited by knocking down multi‐drug resistance protein 4 (MRP4)
Author(s) -
Coleman Amy M.,
Goldmeyer James,
Renfro J. Larry
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.a592-c
Subject(s) - secretion , reabsorption , apical membrane , epithelial polarity , brush border , chemistry , endocrinology , kidney , proximal tubule , medicine , multidrug resistance associated protein 2 , epithelium , renal physiology , microbiology and biotechnology , vesicle , biology , biochemistry , cell , transporter , membrane , atp binding cassette transporter , genetics , gene
Elevated plasma UA has been implicated in the development of obesity and hypertension as well as the metabolic syndrome. Renal UA elimination is due mainly to tubular secretion in both the mammalian and avian renal systems; however, the mechanism of UA transport across the brush border membrane (BBM) of the intact proximal tubule epithelium during secretion is uncertain. Previous studies of isolated membrane vesicles have implicated electrical‐gradient driven UA transport and more recently MRP4 ( Physiology, 2005, 20:125–133) . Whereas both UA reabsorption and secretion occur in the mammalian proximal tubule, only secretion is present in the avian system. In the latter, MK571, a specific inhibitor of MRP4 in macrophages, inhibited both electrical‐gradient driven UA transport in BBM vesicles and active transepithelial transport by chicken proximal tubule primary monolayer cultures (PTCs). Depolarization of the plasma membrane in intact PTCs, however, failed to inhibit active transepithelial UA secretion. Short hairpin RNA interference effectively knocked down expression of MRP4 mRNA in PTCs and reduced transepithelial urate secretion approximately 80%. Therefore, direct measure of active transepithelial UA secretion in functional proximal tubule epithelium indicates that MRP4 is the dominant apical membrane exit pathway from cell to lumen. Supported by NSF.