Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells
Farnesoid X receptor (FXR) is a ligand-activated transcription factor highly expressed in the liver and kidneys. Activation of FXR decreases organic cation transporter (OCT) 1-mediated clearance of organic cation compounds in hepatocytes. The present study investigated FXR regulation of renal cleara...
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/17/6078 |
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| author | Teerasak Wongwan Varanuj Chatsudthipong Sunhapas Soodvilai |
| author_facet | Teerasak Wongwan Varanuj Chatsudthipong Sunhapas Soodvilai |
| author_sort | Teerasak Wongwan |
| collection | DOAJ |
| description | Farnesoid X receptor (FXR) is a ligand-activated transcription factor highly expressed in the liver and kidneys. Activation of FXR decreases organic cation transporter (OCT) 1-mediated clearance of organic cation compounds in hepatocytes. The present study investigated FXR regulation of renal clearance of organic cations by OCT2 modulation and multidrug and toxin extrusion proteins (MATEs). The role of FXR in OCT2 and MATEs functions was investigated by monitoring the flux of <sup>3</sup>H–MPP<sup>+</sup>, a substrate of OCT2 and MATEs. FXR agonists chenodeoxycholic acid (CDCA) and GW4064 stimulated OCT2-mediated <sup>3</sup>H–MPP<sup>+</sup> uptake in human renal proximal tubular cells (RPTEC/TERT1 cells) and OCT2-CHO-K1 cells. The stimulatory effect of CDCA (20 µM) was abolished by an FXR antagonist, Z-guggulsterone, indicating an FXR-dependent mechanism. CDCA increased OCT2 transport activity via an increased maximal transport rate of MPP<sup>+</sup>. Additionally, 24 h CDCA treatment increased MATEs-mediated <sup>3</sup>H-MPP<sup>+</sup> uptake. Moreover, CDCA treatment increased the expression of OCT2, MATE1, and MATE2-K mRNA compared with that of the control. OCT2 protein expression was also increased following CDCA treatment. FXR activation stimulates renal OCT2- and MATE1/2-K-mediated cation transports in proximal tubules, demonstrating that FXR plays a role in the regulation of OCT2 and MATEs in renal proximal tubular cells. |
| first_indexed | 2024-03-10T16:56:39Z |
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| id | doaj.art-35399a568dd1460fb5ceed3a2545aa23 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:56:39Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-35399a568dd1460fb5ceed3a2545aa232023-11-20T11:07:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012117607810.3390/ijms21176078Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular CellsTeerasak Wongwan0Varanuj Chatsudthipong1Sunhapas Soodvilai2Research Center of Transport Proteins for Medical Innovation, Department of Physiology, Mahidol University, Bangkok 10400, ThailandResearch Center of Transport Proteins for Medical Innovation, Department of Physiology, Mahidol University, Bangkok 10400, ThailandResearch Center of Transport Proteins for Medical Innovation, Department of Physiology, Mahidol University, Bangkok 10400, ThailandFarnesoid X receptor (FXR) is a ligand-activated transcription factor highly expressed in the liver and kidneys. Activation of FXR decreases organic cation transporter (OCT) 1-mediated clearance of organic cation compounds in hepatocytes. The present study investigated FXR regulation of renal clearance of organic cations by OCT2 modulation and multidrug and toxin extrusion proteins (MATEs). The role of FXR in OCT2 and MATEs functions was investigated by monitoring the flux of <sup>3</sup>H–MPP<sup>+</sup>, a substrate of OCT2 and MATEs. FXR agonists chenodeoxycholic acid (CDCA) and GW4064 stimulated OCT2-mediated <sup>3</sup>H–MPP<sup>+</sup> uptake in human renal proximal tubular cells (RPTEC/TERT1 cells) and OCT2-CHO-K1 cells. The stimulatory effect of CDCA (20 µM) was abolished by an FXR antagonist, Z-guggulsterone, indicating an FXR-dependent mechanism. CDCA increased OCT2 transport activity via an increased maximal transport rate of MPP<sup>+</sup>. Additionally, 24 h CDCA treatment increased MATEs-mediated <sup>3</sup>H-MPP<sup>+</sup> uptake. Moreover, CDCA treatment increased the expression of OCT2, MATE1, and MATE2-K mRNA compared with that of the control. OCT2 protein expression was also increased following CDCA treatment. FXR activation stimulates renal OCT2- and MATE1/2-K-mediated cation transports in proximal tubules, demonstrating that FXR plays a role in the regulation of OCT2 and MATEs in renal proximal tubular cells.https://www.mdpi.com/1422-0067/21/17/6078Nuclear receptorrenal excretionkidneydrug transportersbile acids |
| spellingShingle | Teerasak Wongwan Varanuj Chatsudthipong Sunhapas Soodvilai Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells International Journal of Molecular Sciences Nuclear receptor renal excretion kidney drug transporters bile acids |
| title | Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells |
| title_full | Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells |
| title_fullStr | Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells |
| title_full_unstemmed | Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells |
| title_short | Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells |
| title_sort | farnesoid x receptor activation stimulates organic cations transport in human renal proximal tubular cells |
| topic | Nuclear receptor renal excretion kidney drug transporters bile acids |
| url | https://www.mdpi.com/1422-0067/21/17/6078 |
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