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|Title:||Activation of liver X receptor inhibits OCT2-mediated organic cation transport in renal proximal tubular cells|
|Keywords:||Biochemistry, Genetics and Molecular Biology|
|Citation:||Pflugers Archiv European Journal of Physiology. Vol.469, No.11 (2017), 1471-1481|
|Abstract:||© 2017, Springer-Verlag GmbH Germany. Liver X receptor (LXR) is transcriptional factor that plays an important role in the regulation of energy metabolism such as cholesterol, lipid, and glucose metabolism as well as membrane transporters and channels. Using both in vitro and in vivo models, LXR regulation of the expression and function of renal organic cation transporter 2 (OCT2) was observed. Synthetic LXR agonist (GW3965) and endogenous LXR agonist (22R-hydroxycholesterol) significantly reduced the uptake of 3H–MPP+, a prototypic substrate of OCT2, in both OCT2- Chinese hamster ovary K1 and human renal proximal tubular cells (RPTEC/TERT1). GW3965 decreased transport activity of OCT2 via a reduction of the maximal transport rate of MPP+ without affecting transporter affinity. The inhibitory effect of GW3965 was attenuated by co-treatment with LXR antagonist (fenofibrate) indicating the inhibition was LXR-dependent mechanism. In addition, co-treatment with a retinoic X receptor (RXR) ligand, 9-cis retinoic acid enhanced the inhibitory effect of GW3965, indicating negative regulation of OCT2 transport activity by the LXR/RXR complex. Treatment RPTEC/TERT1 cells with GW3965 significantly reduced OCT2 protein expression without changing mRNA expression. In parallel, the effect of LXR activation on OCT2 function was investigated in intact mouse kidney. Treating mice with 50 mg/kg BW T0901317 for 14 days significantly decreased 3H–MPP+ uptake into renal cortical slices, correlating with decreased OCT2 protein expression in renal cortex without changes in mRNA expression levels. Taken together, LXR/RXR activation downregulates the protein expression and function of OCT2 in renal proximal tubule, suggesting LXR might affect the total profile of renal excretion of cationic compounds.|
|Appears in Collections:||Scopus 2016-2017|
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