Effects of Sex and Cross-Sex Hormone Treatment on Renal MCT/SMCT Expression Following Prepubertal Gonadectomy

Background: Kidney proton- and sodium-dependent monocarboxylate transporters (MCT/SMCT) are involved in the renal reabsorption of substrates, and thus factors involved in their regulation may have pharmacokinetic implications. Previous studies have demonstrated sex hormone-dependent regulation of MCTs and SMCTs in tissues involved in drug disposition. The present study evaluates the impact of puberty on renal MCT/SMCT expression with ovariectomy and castration conducted before puberty, removing the initial exposure to sex hormones. Methods: Male and female rats were castrated or ovariectomized before puberty (4 weeks of age), and subsequently treated with testosterone, 17β-estradiol, progesterone, or both 17β-estradiol and progesterone for 21 days starting at 10 weeks of age. MCT1, CD147, and SMCT1 membrane-bound kidney expression were quantified by Western blot. Results: SMCT1 and CD147 expression were significantly higher in OVX and CST rats treated with testosterone, and testosterone plasma concentrations showed a significant positive correlation with MCT1, SMCT1, and CD147 expression. CD147 expression was significantly downregulated in OVX rats treated with estrogen, compared to placebo controls, and estrogen plasma concentrations were significantly negatively correlated with CD147 expression. Conclusions: Sex and cross-sex hormone treatment altered MCT1, CD147, and SMCT1 expression when gonadectomy was conducted before puberty. The magnitude and direction of the expression differences differed when compared to animals that underwent gonadectomy after puberty, suggesting that sex hormone exposure during puberty plays a key role in MCT1/SMCT1 renal expression. Further studies are needed to elucidate the underlying mechanisms for the differential regulation of MCTs/SMCTs when gonadectomy occurs before or after puberty.