Sex-specific Regulation of ENaC and Androgen Receptor in Female Rat Kidney

With the beginning of puberty blood pressure increases and is persistently higher in men than in premenopausal women. Sex steroids are known to have complex effects on the renal and cardiovascular system and are involved in blood pressure regulation. The epithelial sodium channel (ENaC) modulates sodium reabsorption in the kidney, but little is known about sex-specific regulation of ENaC subunit expression. Regulation of the androgen receptor (AR) is known to be tissue-specific and age-dependent, but not well studied in the kidney. We investigated the effects of sex steroids on ENaC subunits and renal AR expression in an in vivo rat model. Ovariectomized female Wistar rats were treated with placebo, testosterone, 5 alpha-dihydrotestosterone (DHT) or 17 beta-estradiol (E2) for 14 days, and quantitative PCR and Western immunoblots were performed. DHT significantly decreased expression of all ENaC subunits in female rats, whereas testosterone showed only a trend to lower ENaC expression. These results are in contrast to previous studies where stimulating effects of androgens on the alpha-subunit of ENaC were seen. AR mRNA expression showed a trend to lower levels in females after testosterone treatment in this study. However, estrogen treatment significantly downregulated AR mRNA expression. In male control animals we were able to show a significantly increased expression of AR mRNA upon testosterone treatment. Our data demonstrate that AR and ENaC are regulated by sex steroids. That way sex steroids might modulate renal sodium reabsorption and therefore provide a possible explanation for sex differences in blood pressure.