Regulation of mouse renal CYP2J5 expression by sex hormones.

Abstract

Mouse CYP2J5 is abundant in kidney and active in the metabolism of arachidonic acid to epoxyeicosatrienoic acids. Western blots of microsomes prepared from mouse kidneys demonstrate that after puberty, CYP2J5 protein is present at higher levels in male mice than in female mice. Northern analysis reveals that CYP2J5 transcripts are more abundant in adult male versus female kidneys, indicating that gender differences in renal CYP2J5 expression are regulated at a pretranslational level. Castration of male mice results in decreased renal CYP2J5 expression, and treatment of castrated male mice or female mice with 5alpha-dihydrotestosterone increases expression to levels that approximate those in intact male mice. In contrast, treatment of ovariectomized female mice or castrated male mice with 17beta-estradiol causes a further reduction in CYP2J5 expression. Growth hormone-deficient (lit/lit) mice respond similarly to castration and 5alpha-dihydrotestosterone treatment, indicating that the androgen effects are not mediated by alterations in the growth hormone secretory pattern. Mice that lack a functional androgen receptor (Tfm hemizygous) have reduced levels of renal CYP2J5 and do not respond to 5alpha-dihydrotestosterone treatment. Similarly, wild-type male mice treated with flutamide, an androgen antagonist, exhibit reduced renal CYP2J5 levels. Female estrogen receptor-alpha knockout (alphaERKO) mice, which are known to have elevated circulating testosterone levels, have significantly increased renal CYP2J5 expression compared with wild-type female mice, and these differences are abrogated by ovariectomy or treatment with flutamide. Based on these data, we conclude that the renal expression of CYP2J5 is up-regulated by androgen and down-regulated by estrogen.