Hormonal regulation of organic cation transporter OCT2 expression in rat kidney

Urakami, Yumiko; Okuda, Masahiro; Saya, Hideyuki; Inui, Ken Ichi

doi:10.1016/s0014-5793(00)01525-8

Cited by 134 publications

(108 citation statements)

References 26 publications

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“…Considering the results in the experiment 2 that there was no difference in blood L-FABP, Cys-C, β2-MG, and glucose levels between the sham-operated and orchidectomized male rats, it was indicated testosterone was involved in the reabsorption process. In the kidney, there are receptors and transporters such as sodium/glucose co-transporter-2 and organic cation transporter 2, which have been reported that testosterone changed their expression levels in rats (Pávó et al, 1995;Urakami et al, 2000;Ljubojevic et al, 2004;Sabolic et al, 2012;Loh et al, 2017). Meanwhile, sex differences of megalin and cubilin, receptors related to reabsorption of LMWPs and albumin which are localized in the renal proximal tubules (Cui et al, 1996;Orlando et al, 1998;Birn et al, 2000;Oyama et al, 2005;Hvidberg et al, 2005;Kaseda et al, 2007;Amsellem et al, 2010), have been ambiguous.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

et al. 2017

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-Urinary biomarkers have been used widely in preclinical toxicity studies to detect dysfunctions and injuries of the kidney caused by drugs under development. While they have been well studied for evaluating nephrotoxicity, knowledge of sex differences in excretion levels of urinary biomarkers remains inadequate. We conducted experiments focused on effects of endogenous sex hormones on urinary biomarkers using intact and castrated male and female rats. Comparisons of the urinary biomarker excretion levels between intact male and female rats at 5, 7, 9 and 12 weeks of age revealed higher excretion levels of leucine aminopeptidase (LAP), γ-glutamyl transpeptidase (γGTP), total protein, liver-type fatty acid-binding protein (L-FABP), cystatin C (Cys-C) and β2-microglobulin (β2-MG), and lower excretion level of kidney injury molecule 1 (Kim-1), in male rats as compared to female rats. Orchidectomized male rats showed lower urinary excretion levels of alkaline phosphatase (ALP), LAP, γGTP, N-acetyl-β-D-glucosaminidase (NAG), glucose, total protein, L-FABP, Cys-C, β2-MG and neutrophil gelatinaseassociated lipocalin (NGAL), and higher urinary excretion levels of clusterin (CLU) and Kim-1, than sham-operated male rats. On the other hand, no significant differences in the urinary biomarker excretion levels excluding ALP were observed between ovariectomized and sham-operated female rats. In the present study, we demonstrated the existence of sex differences in excretion levels of urinary biomarkers that are universally used in preclinical toxicity studies, and also that these differences, especially in relation to the urinary excretions of ALP, LAP, γGTP, total protein, L-FABP, Cys-C, and β2-MG, may closely relate to the endogenous testosterone.

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Section: Discussionmentioning

confidence: 99%

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

et al. 2017

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“…Recently, it was reported that the expression of rOCT2 was decreased in rats with chronic renal failure (Ji et al, 2002), hyperuricemia (Habu et al, 2003), and diabetes mellitus (Thomas et al, 2004). Urakami et al (2000) reported that the expression of rOCT2 was up-regulated by testosterone and down-regulated by estradiol in rats. It was also suggested that the lowered plasma level of testosterone was responsible for the decreased rOCT2 expression (Ji et al, 2002).…”

Section: Downloaded Frommentioning

confidence: 99%

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

Matsuzaki

Morisaki²,

Sugimoto³

et al. 2008

Drug Metab Dispos

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ABSTRACT:In the proximal tubules of rat (r) kidney, the polyspecific organic cation transporters (OCTs), rOCT1 and rOCT2, mediate the basolateral uptake of various organic cations, including many drugs, toxins, and endogenous compounds, and the apical type of H ؉ / organic cation antiporter, rat multidrug and toxin extrusion 1 (rMATE1), mediate the efflux of organic cations. Renal clearances of H 2 receptor antagonists, including famotidine, were reported to be decreased in patients with kidney disease. Therefore, acute kidney injury (AKI) could influence renal excretion and disposition of organic cations accompanied by the regulation of organic cation transporters. The aim of this study was to investigate the pharmacokinetic alteration of cationic drugs and the expression of tubular organic cation transporters, rOCT1, rOCT2, and rMATE1, in ischemia/reperfusion (I/R)-induced AKI rats. I/R-induced AKI increased the plasma concentration of i.v. administrated famotidine, a substrate for rOCT1 and rOCT2, or tetraethylammonium (TEA), a substrate for rOCT1, rOCT2, and rMATE1. The areas under the plasma concentration curves for famotidine and TEA were 2-and 6-fold higher in I/R rats than in sham-operated rats, respectively. The accumulation of TEA into renal slices was significantly decreased, suggesting that organic cation transport activity at the basolateral membranes was reduced in I/R rat kidney. The protein expressions of basolateral rOCT2 and luminal rMATE1 were down-regulated in I/R rat kidneys. These data suggest that the urinary secretion of cationic drugs via epithelial organic cation transporters is decreased in AKI.

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“…Therefore, the gender differences in lactate levels are more likely related to the fundamental difference in sex hormone levels in males and females. Urakami demonstrated in rats that OCT2 is responsible for the gender differences in renal basolateral membrane OCT activity, and OCT2, but not OCT1, is sexually up-regulated by testosterone and down-regulated by estradiol in the kidney [8][9][10] . In our clinical study of 1021 patients with T2DM, we observed that blood lactate levels were due to gender differences, with females having significantly higher blood lactate levels than males treated with metformin (unpublished data).…”

Section: Metformin (N=200)mentioning

confidence: 99%

“…A kinetic analysis of metformin transport and its distribution in rats suggested that metformin is a superior substrate for renal OCT2 rather than hepatic OCT1, and renal OCT2 plays a dominant role in metformin pharmacokinetics [4] . In addition, OCT2 is responsible for the observed gender differences in SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin www.chinaphar.com Li Q et al Acta Pharmacologica Sinica npg renal basolateral membrane organic cation transporting activity [7][8][9] ; however, to date no studies related to human OCT2 and its relevance to metformin-treatment in diabetic populations have been reported.…”

Section: Introductionmentioning

confidence: 99%

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

Liu

Zheng

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the potential relationship between the SLC22A2 gene polymorphism and blood lactate concentration in Shanghai Hans suffering from type 2 diabetes mellitus (T2DM). Methods: The SLC22A2 single nucleotide polymorphism (SNP) 808G/T was genotyped in 400 T2DM patients, including a metformintreated group (n=200) and a non-metformin-treated group (n=200). Fasting plasma lactic acid levels were measured with an enzymeelectrode assay. Biochemical indexes, including plasma alanine aminotransferase (ALT), creatinine (Cr), and glycolated hemoglobin (HbA1c), were also measured. Results: The fasting plasma lactate concentration in the metformin-treated group was significantly higher than that in the non-metformin-treated group (1.29±0.45 mmol/L vs 1.18±0.44 mmol/L, P=0.015). Additionally, the ratio of patients with hyperlactacidemia was 8% (16/200) for the metformin-treated group and 5.5% (11/200) for the non-metformin-treated group, with no lactic acidosis found in either group. The frequency of the SLC22A2 808G/T T allele was 12.9%. Patients with the mutant genotype (TT) had a higher blood lactate concentration in the metformin-treated group than those in the non-metformin-treated group (t=2.492, P=0.013). This trend was not observed in the GG and GT genotypes when compared with metformin-treated and non-metformin-treated groups. Patients with the mutant genotype (TT) in the metformin-treated group also had a higher incidence of hyperlactacidemia compared with the GG genotype (40.0% vs 6.9%, P=0.050) in the metformin-treated group and the GG (6.0%, P=0.042) or GT (4.3%, P=0.043) genotypes in the non-metformin-treated group. In the metformin-treated group, there were significant gender differences in lactate concentrations in the TT (2.18±0.15 vs 1.04±0.27 mmol/L, P=0.008) and GG genotypes (1.40±0.51 vs 1.19±0.35 mmol/L, P=0.004). The lactate levels of women with the TT genotype were the highest in the metformin-treated group, but differences in lactate levels among the genotypes were not observed in the non-metformin-treated group. Conclusion: There is an 808G/T polymorphism in the SLC22A2 gene in Chinese Hans with T2DM. The 808G>T variance in the SLC22A2 gene can affect the plasma lactate level and the incidence of hyperlactacidemia in T2DM patients undergoing metformin therapy. Additionally, the female patients carrying the TT genotype are prone to lactatemia.

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Hormonal regulation of organic cation transporter OCT2 expression in rat kidney

Cited by 134 publications

References 26 publications

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

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

SLC22A2 gene 808 G/T variant is related to plasma lactate concentration in Chinese type 2 diabetics treated with metformin

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