Global transcription profiling of estrogen activity: Estrogen receptor a regulates gene expression in the kidney

Estrogen receptors (ERs) are expressed in numerous organs, although only a few organs are considered classical targets for estrogens. We have completed a systematic survey of estrogen regulation of approximately 10,000 genes in 13 tissues from wild-type and ERbetaKO mice treated sc with vehicle or 17beta-estradiol (E2) for 6 wk. The uterus and pituitary had the greatest number of genes regulated by E2, whereas the kidney had the third largest number of regulated genes. In situ hybridizations localized E2 regulation in the kidney to the juxtamedullary region of the cortex in both the mouse and rat. The ED50 for gene inductions in the kidney was 3 mug/kg(.)d, comparable with the 2.4 mug/kg(.)d ED50 for c-fos induction in the uterus. E2 regulations in the kidney were intact in ERbetaKO mice, and the ERalpha-selective agonist propylpyrazole triol acted similarly to E2, together suggesting an ERalpha-mediated mechanism. Several genes were induced within 2 h of E2 treatment, suggesting a direct activity of ERalpha within the kidney. Finally, the combination of the activation function (AF)1-selective agonist tamoxifen plus ERalphaKO(CH) mice expressing an AF1-deleted version of ERa allowed delineation of genes with differing requirements for AF1 or AF2 activity in the kidney.