Different effect of testosterone and oestrogen on urinary excretion of metformin via regulating OCTs and MATEs expression in the kidney of mice

Abstract

The aim of this study was to investigate the effect of testosterone and oestrogen on regulating organic cation transporters (Octs) and multidrug and toxin extrusions (Mates) expression in the kidney of mice and urinary excretion of metformin. 8 week‐old male db/db mice were treated with estradiol (5 mg/kg), testosterone (50 mg/kg) or olive oil with same volume. Metformin (150 mg/kg) was injected in daily for successive 7 days. Plasma, urine and tissue concentrations of metformin were determined by liquid chromatography‐tandem mass spectrometry (LCMS) assay. Western blotting and Real‐time PCR analysis were successively used to evaluate the renal protein and mRNA expression of Octs and MATEs. After treatment, the protein expression of Mate1 and Oct2 in testosterone group was significantly increased than those in control group (both P < 0.05). The protein expression of Mate1 and Oct2 in estradiol group was significantly reduced by 29.4% and 43.3%, respectively, compared to those in control group (all P < 0.05). These data showed a good agreement with the change in mRNA level (all P < 0.05). The plasma metformin concentration (ng/ml) in mice treated with estradiol was significantly higher than control and testosterone group (677.56 ± 72.49 versus 293.92 ± 83.27 and 261.46 ± 79.45; P < 0.01). Moreover, testosterone increased the metformin urine excretion of mice while estradiol decreasing (both P < 0.01). Spearman correlation analysis showed that gonadal hormone was closely associated with Mate1 and Oct2 expression and metformin urine excretion in db/db mice (all P < 0.05). Testosterone and oestrogen exerted reverse effect on metformin urinary excretion via regulating Octs and Mates expression in the kidney of mice.

Thioacetamide-Induced Acute Liver Injury Increases Metformin Plasma Exposure by Downregulating Renal OCT2 and MATE1 Expression and Function

“…Subsequently, we cultured HK-2 cells with these abnormally changed substances. The results demonstrate that TNF-α dose-dependently reduces the renal expression of MATE1 while estrogen dose-dependently reduces the renal expression of OCT2, which is in line with reported research [26,29]. These findings imply that TNF-α and estrogen may play crucial roles in decreasing the expression of MATE1 and OCT2, respectively.…”

“…In a rat model of hyperuricemia, the mRNA levels of MATE1 and OCT2 were decreased, leading to an increased accumulation of metformin in kidney tissue [28]. The protein expression of MATE1 and OCT2 was reported to be decreased in mice treated with estradiol and the plasma of metformin was significantly elevated [29]. Liver injury can lead to disorders of various endogenous substances, including the production of inflammatory factors, sex hormone metabolism disorders, and reduced ammonia clearance.…”

Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

“…Furthermore, He at al. found that kidney expression of MATE1 could be modified by treatment with testosterone or estradiol, compared to olive oil as a control 44 .…”

MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia

“…Interestingly, the interaction liability for dofetilide with verapamil was sexually dimorphic ( Supplementary Figure S2D,E and Table S3 ). Although hormone-dependent regulatory mechanisms have been reported for renal organic cation transporters [ 47 , 48 ], and MATE1 expression is higher in the kidney of male mice ( Supplementary Figure S1C ), the clinical ramification of this sex-dependent influence of verapamil on the pharmacokinetics of dofetilide remains unclear.…”