PT  - JOURNAL ARTICLE
AU  - Aishwarya Jayagopal
AU  - Paul R. Brakeman
AU  - Peter Soler
AU  - Nicholas Ferrell
AU  - William Fissell
AU  - Deanna L. Kroetz
AU  - Shuvo Roy
TI  - Apical Shear Stress Enhanced Organic Cation Transport in Human OCT2/MATE1-Transfected Madin-Darby Canine Kidney Cells Involves Ciliary Sensing
AID  - 10.1124/jpet.118.255026
DP  - 2019 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 523--530
VI  - 369
IP  - 3
4099  - http://jpet.aspetjournals.org/content/369/3/523.short
4100  - http://jpet.aspetjournals.org/content/369/3/523.full
SO  - J Pharmacol Exp Ther2019 Jun 01; 369
AB  - Active 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 flow-induced 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/cm2), cells showed a corresponding increase in transport of ASP+, reaching a maximal 4.2-fold increase at 2 dynes/cm2 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/cm2 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.