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Apical Shear Stress Enhanced Organic Cation Transport in Human OCT2/MATE1-Transfected Madin-Darby Canine Kidney Cells Involves Ciliary Sensing

dc.contributor.authorJayagopal, Aishwarya
dc.contributor.authorBrakeman, Paul R.
dc.contributor.authorSoler, Peter
dc.contributor.authorFerrell, Nicholas
dc.contributor.authorFissell, William
dc.contributor.authorKroetz, Deanna L.
dc.contributor.authorRoy, Shuvo
dc.identifier.othereISSN: 1521-0103
dc.description.abstractActive transport by renal proximal tubules plays a significant role in drug disposition. During drug development, estimates of renal excretion are essential to dose determination. Kidney bioreactors that reproduce physiologic cues in the kidney, such as flowinduced shear stress, may better predict in vivo drug behavior than do current in vitro models. In this study, we investigated the role of shear stress on active transport of 4-(4-(dimethylamino)-styryl)-N-methylpyridinium iodide (ASP+) by Madin-Darby canine kidney cells exogenously expressing the human organic cation transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1). Cells cultured in a parallel plate under continuous media perfusion formed a tight monolayer with a high barrier to inulin. In response to increasing levels of shear stress (0.2-2 dynes/cm(2)), cells showed a corresponding increase in transport of ASP+, reaching a maximal 4.2-fold increase at 2 dynes/cm(2) compared with cells cultured under static conditions. This transport was inhibited with imipramine, indicating active transport was present under shear stress conditions. Cells exposed to shear stress of 2 dynes/cm2 also showed an increase in RNA expression of both transfected human and endogenous OCT2 (3.7- and 2.0-fold, respectively). Removal of cilia by ammonium sulfate eliminated the effects of shear on ASP+ transport at 0.5 dynes/cm(2) with no effect on ASP+ transport under static conditions. These results indicate that shear stress affects active transport of organic cations in renal tubular epithelial cells in a cilia-dependent manner.en_US
dc.description.sponsorshipThis work was supported by National Institutes of Health National Institute of Biomedical Imaging and Bioengineering [Grants U01EB021214, R01EB014315] and the National Institute of Diabetes and Digestive and Kidney Diseases [Grant K01DK092357]; the Defense Threat Reduction Agency [Grant CBMXCEL-XL1-2-001]; the National Science Foundation Graduate Student Research Fellowship; and the Patterson-Barclay Foundation and the Wildwood Foundation.en_US
dc.publisherJournal of Pharmacology and Experimental Therapeuticsen_US
dc.rightsThis article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on March 25, 2019 as DOI: 10.1124/jpet.118.25502
dc.titleApical Shear Stress Enhanced Organic Cation Transport in Human OCT2/MATE1-Transfected Madin-Darby Canine Kidney Cells Involves Ciliary Sensingen_US

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