TY - JOUR T1 - Apical Shear Stress Enhanced Organic Cation Transport in hOCT2/hMATE1 Transfected MDCK Cells Involves Ciliary Sensing JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.255026 SP - jpet.118.255026 AU - Aishwarya Jayagopal AU - Paul Brakeman AU - Peter Soler AU - Nicholas Ferrell AU - William Fissell AU - Deanna L Kroetz AU - Shuvo Roy Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/03/25/jpet.118.255026.abstract N2 - 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 physiological cues in the kidney, such as flow-induced shear stress, may better predict in vivo drug behavior than current in vitro models. In this study, the role of shear stress on active transport of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP+) by MDCK cells exogenously expressing the human organic cation transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) was investigated. Cells cultured in a parallel plate under continuous media perfusion formed a tight monolayer with 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 when compared to 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. ER -