Wedelolactone protects against cisplatin-induced nephrotoxicity in mice via inhibition of organic cation transporter 2

The balance of cisplatin uptake and efflux, mediated mainly by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1), respectively, determines the renal accumulation and nephrotoxicity of cisplatin. Using transporter-mediated cellular uptake assay, we identified wedelolactone (WEL), a medicinal plant-derived natural compound, is a competitive inhibitor of OCT2 and a noncompetitive inhibitor of MATE1. Wedelolactone showed a selectivity to inhibit OCT2 rather than MATE1. Cytotoxicity studies revealed that wedelolactone alleviated cisplatin-induced cytotoxicity in OCT2-overexpressing HEK293 cells, whereas it did not alter the cytotoxicity of cisplatin in various cancer cell lines. Additionally, wedelolactone altered cisplatin pharmacokinetics, reduced kidney accumulation of cisplatin, and ameliorated cisplatin-induced acute kidney injury in the Institute of Cancer Research mice. In conclusion, these findings suggest a translational potential of WEL as a natural therapy for preventing cisplatin-induced nephrotoxicity and highlight the need for drug–drug interaction investigations of WEL with other treatments which are substrates of OCT2 and/or MATE1.

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The Role of NF-kB in the Downregulation of Organic Cation Transporter 2 Expression and Renal Cation Secretion in Kidney Disease

Frontiers in Medicine ◽

10.3389/fmed.2021.800421 ◽

2022 ◽

Vol 8 ◽

Author(s):

Chao Han ◽

Juan Zheng ◽

Fengyi Wang ◽

Qingyang Lu ◽

Qingfa Chen ◽

...

Keyword(s):

Kidney Disease ◽

Organic Cation ◽

Rat Kidney ◽

Basolateral Membrane ◽

Kidney Injury ◽

Organic Cation Transporter ◽

Tubular Secretion ◽

Gene Reporter Assay ◽

Organic Cation Transporter 2

Organic cation transporter 2 (OCT2), encoded by the SLC22A2 gene, is the main cation transporter on the basolateral membrane of proximal tubular cells. OCT2 facilitates the entry step of the vectorial transport of most cations from the peritubular space into the urine. OCT2 downregulation in kidney disease models is apparent, yet not clear from a mechanistic vantage point. The aim of this study was to explore the role of inflammation, a common thread in kidney disease, and NF-kB in OCT2 modulation and tubular secretion. Among the OCTs, OCT2 was found consistently downregulated in the kidney of rats with chronic kidney disease (CKD) or acute kidney injury (AKI) and in patients diagnosed with CKD, and it was associated with the upregulation of TNFα renal expression. Exposure to TNFα reduced the expression and function of OCT2 in primary renal proximal tubule epithelial cells (RPTEC). Silencing or pharmacological inhibition of NF-kB rescued the expression of OCT2 in the presence of TNFα, indicating that OCT2 repression was NF-kB-dependent. In silico prediction coupled to gene reporter assay demonstrated the presence of at least one functional NF-kB cis-element upstream the transcription starting site of the SLC22A2 gene. Acute inflammation triggered by lipopolysaccharide injection induced TNFα expression and the downregulation of OCT2 in rat kidney. The inflammation did reduce the active secretion of the cation Rhodamine 123, with no impairment of the glomerular filtration. In conclusion, the NF-kB pathway plays a major role in the transcriptional regulation of OCT2 and, in turn, in the overall renal secretory capacity.

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Substrate-Dependent Trans-Stimulation of Organic Cation Transporter 2 Activity

International Journal of Molecular Sciences ◽

10.3390/ijms222312926 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12926

Author(s):

Charles R. Lefèvre ◽

Marc Le Vée ◽

Sophie Gaubert ◽

Elodie Jouan ◽

Arnaud Bruyere ◽

...

Keyword(s):

Molecular Weight ◽

Drug Toxicity ◽

Organic Cation ◽

Molecular Descriptors ◽

Organic Cation Transporter ◽

Hek293 Cells ◽

Ic50 Values ◽

Organic Cation Transporter 2 ◽

Low Sensitivity ◽

Stimulation Of

The search of substrates for solute carriers (SLCs) constitutes a major issue, owing notably to the role played by some SLCs, such as the renal electrogenic organic cation transporter (OCT) 2 (SLC22A2), in pharmacokinetics, drug–drug interactions and drug toxicity. For this purpose, substrates have been proposed to be identified by their cis-inhibition and trans-stimulation properties towards transporter activity. To get insights on the sensitivity of this approach for identifying SLC substrates, 15 various exogenous and endogenous OCT2 substrates were analysed in the present study, using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (DiASP) as a fluorescent OCT2 tracer substrate. All OCT2 substrates cis-inhibited DiASP uptake in OCT2-overexpressing HEK293 cells, with IC50 values ranging from 0.24 µM (for ipratropium) to 2.39 mM (for dopamine). By contrast, only 4/15 substrates, i.e., acetylcholine, agmatine, choline and metformin, trans-stimulated DiASP uptake, with a full suppression of the trans-stimulating effect of metformin by the reference OCT2 inhibitor amitriptyline. An analysis of molecular descriptors next indicated that trans-stimulating OCT2 substrates exhibit lower molecular weight, volume, polarizability and lipophilicity than non-trans-stimulating counterparts. Overall, these data indicated a rather low sensitivity (26.7%) of the trans-stimulation assay for identifying OCT2 substrates, and caution with respect to the use of such assay may therefore be considered.

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Altered Pharmacokinetics of Cationic Drugs Caused by Down-Regulation of Renal Rat Organic Cation Transporter 2 (Slc22a2) and Rat Multidrug and Toxin Extrusion 1 (Slc47a1) in Ischemia/Reperfusion-Induced Acute Kidney Injury

Drug Metabolism and Disposition ◽

10.1124/dmd.107.019869 ◽

2008 ◽

Vol 36 (4) ◽

pp. 649-654 ◽

Cited By ~ 36

Author(s):

Takanobu Matsuzaki ◽

Takafumi Morisaki ◽

Wakako Sugimoto ◽

Koji Yokoo ◽

Daisuke Sato ◽

...

Keyword(s):

Acute Kidney Injury ◽

Organic Cation ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Organic Cation Transporter ◽

Down Regulation ◽

Cationic Drugs ◽

Organic Cation Transporter 2 ◽

Toxin Extrusion

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In Vitro Inhibition of Renal OCT2 and MATE1 Secretion by Antiemetic Drugs

International Journal of Molecular Sciences ◽

10.3390/ijms22126439 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6439

Author(s):

Blessy George ◽

Xia Wen ◽

Edgar A. Jaimes ◽

Melanie S. Joy ◽

Lauren M. Aleksunes

Keyword(s):

Organic Cation ◽

Mdck Cells ◽

Organic Cation Transporter ◽

Hek293 Cells ◽

Intracellular Accumulation ◽

Renal Secretion ◽

Transcellular Transport ◽

Antiemetic Drugs ◽

Organic Cation Transporter 2

The organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) mediate the renal secretion of drugs. Recent studies suggest that ondansetron, a 5-HT3 antagonist drug used to prevent nausea and vomiting, can inhibit OCT2- and MATE1-mediated transport. The purpose of this study was to test the ability of five 5-HT3 antagonist drugs to inhibit the OCT2 and MATE1 transporters. The transport of the OCT2/MATE1 probe substrate ASP+ was assessed using two models: (1) HEK293 kidney cells overexpressing human OCT2 or MATE1, and (2) MDCK cells transfected with human OCT2 and MATE1. In HEK293 cells, the inhibition of ASP+ uptake by OCT2 listed in order of potency was palonosetron (IC50: 2.6 μM) > ondansetron > granisetron > tropisetron > dolasetron (IC50: 85.4 μM) and the inhibition of ASP+ uptake by MATE1 in order of potency was ondansetron (IC50: 0.1 μM) > palonosetron = tropisetron > granisetron > dolasetron (IC50: 27.4 μM). Ondansetron (0.5–20 μM) inhibited the basolateral-to-apical transcellular transport of ASP+ up to 64%. Higher concentrations (10 and 20 μM) of palonosetron, tropisetron, and dolasetron similarly reduced the transcellular transport of ASP+. In double-transfected OCT2-MATE1 MDCK cells, ondansetron at concentrations of 0.5 and 2.5 μM caused significant intracellular accumulation of ASP+. Taken together, these data suggest that 5-HT3 antagonist drugs may inhibit the renal secretion of cationic drugs by interfering with OCT2 and/or MATE1 function.

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