Activation of farnesoid X receptor stimulates OCT2 function in human renal proximal tubular cells

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Farnesoid X receptor (FXR) is a member of the nuclear receptor subfamily which highly expresses in liver, intestine, and kidney. It plays an essential role in maintaining of bile acids, glucose and lipid homeostasis. Previous reports showed cholestatic condition‐induced chenodeoxycholic acid (CDCA) inhibited organic cation transporter 1 (OCT1) in human and rat liver. However, there is still lack the information concerning the effects of FXR on expression and transport function of renal OCT2 which plays a major role in the renal elimination of cationic compounds. In this study, we investigated whether FXR activation regulates OCT2 in human renal proximal tubular cells. Treatment human renal proximal tubular cells (RPTEC/TERT1 cell) with FXR agonists, 10–100 μM CDCA and 1 μM GW4064, for 24 hours significantly increased intracellular accumulation of 3H‐MPP+, a prototypic substrate of OCT2. The stimulatory effect of FXR agonists was attenuated by co‐treatment with FXR antagonist, Z‐guggulsterone (10 μM) indicating the effect of FXR agonist was mediated by FXR‐dependent mechanism. Kinetic study revealed that CDCA increased OCT2 transport activity by increasing the maximal transport rate (Jmax) of 3H‐MPP+ with no significant effect on its affinity. CDCA treatment at both physiological level (20 μM) and cholestatic condition (80 μM) significantly increased mRNA expression of OCT2. In conclusion, FXR activation by both endogenous and synthetic ligands stimulates renal OCT2 transport function in the proximal tubules at least at transcriptional regulation. FXR activation might play a role in the regulation of renal OCT2 in both a physiological and pathological conditions.Support or Funding InformationThis study was supported by grant from the Royal Golden Jubilee (RGJ; grant no. PHD/0238/2553).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.