Research ArticlesMonocarboxylate Transporter Mediates Uptake of Lovastatin Acid in Rat Cultured Mesangial Cells
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INTRODUCTION
Mesangial cells are a major constituent of the renal glomerulus and have complex biological functions. Their proliferation is believed to play an important role in the inflammatory response to glomerular injury, which is one of the general characteristics of various glomerular diseases, including proliferative glomerulonephritis, IgA nephropathy, and diabetic nephropathy.1., 2., 3. However, the mechanisms underlying the occurrence and development of proliferative nephritis remain unclear, being
Materials
Lovastatin was generously provided by Merck Sharp & Dohme Research Laboratories, Rahway, NJ. Lovastatin acid was prepared from its lacton form by hydrolysis in a 0.05 N NaOH solution with stirring at 20°C for 30 min. The hydrolyzed solution was adjusted to pH 7.4 with 0.2 N HCl and then stored at 4°C until use.4,11 The purity of lovastatin acid was >95%, as confirmed by high-performance liquid chromatography (HPLC). RPMI1640 medium, collagenase type I, and FBS were purchased from GIBCO
Expression of mRNAs for MCT Isoforms
The expression of mRNAs for MCT1, 2, 3, and 4 in rat cultured mesangial cells was examined by the RT-PCR method using specific primers for each isoform. As shown in Figure 1, there were mRNAs of MCT1, 2, and 4 in the mesangial cells.
Effect of Extracellular pH
The effect of the extracellular pH on lovastatin acid uptake by mesangial cells is shown in Figure 2. The rate of uptake of lovastatin acid apparently increased with decreasing extracellular pH, the maximum uptake rate being observed at pH 5.5. So, in the following
DISCUSSION
In our previous report,4 the carrier-mediated uptake of lovastatin acid by mesangial cells was estimated to be ∼90% of the total uptake, and contribution of nonspecific diffusion was thought to be negligible. Thus, we consider the results obtained in this study almostly reflect the carrier-mediated uptake of lovastatin acid by mesangial cells.
First, we confirmed the expression of MCT isoform(s) in rat cultured mesangial cells. As shown in Figure 1, there were messages for mRNAs of MCT1, 2, and
ACKNOWLEDGEMENTS
We are grateful to Merck Sharp & Dohme Research Laboratories for generously providing us with the lovastatin.
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2017, Pharmacology and TherapeuticsCitation Excerpt :Carriers of missense mutations of MCT1 may present muscle cramps, fatigue and elevations of serum CK with exercise (Merezhinskaya et al., 2000). The uptake of lovastatin acid into rat mesangial and bovine kidney BNL-1 cells is pH dependant and carried out mostly by MCT4, and secondarily by MCT1; moreover, lovastatin acid dose-dependently inhibits lactic acid uptake by MCT4 (Nagasawa et al., 2003, 2002). In human rhabdomyosarcoma cells, pravastatin inhibits MCT1 uptake and MCT4 efflux of lactic acid by 42% and 21%, respectively (Kobayashi, Fujita, Itagaki, Hirano, & Iseki, 2005).
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2016, European Journal of PharmacologyCitation Excerpt :For SLC16A3, we have demonstrated that the membrane protein is a pH-dependent transporter and is inhibited by HMG-CoA reductase inhibitors (Kobayashi et al., 2006; Sasaki et al., 2013). Nagasawa et al. (2002, 2003) reported that lovastatin may be taken up by SLC16A3. However, there is no report showing that atorvastatin is an inhibitor of SLC16A1, which belongs to the same family as SLC16A3.
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2009, Drug Metabolism and PharmacokineticsTransepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers
2008, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :It was reported that various subtypes of MCT, such as MCT1, MCT3, MCT4, MCT5 and MCT6, are expressed in Caco-2 cells [40]. MCTs are well known to transport short-chain fatty acid and carboxylic acid type of drugs [41]. The key components of substrates for MCTs are thought to be monoanionic carboxylic acid group and nonpolar side chain or aromatic hydrophobic moiety [42].