Estrogen Regulates the Stage-Specific Expression of Kidney Androgen-Regulated Protein in Rat Uterus during Reproductive Cycle and Pregnancy

The female sex steroid, estrogen, acting through its nuclear receptor profoundly influences growth and differentiation programs in the mammalian uterus by regulating the expression of specific cellular genes. The identity and profile of expression of the estrogen-regulated genes at various stages of the reproductive cycle and pregnancy, however, remain largely unknown. Using a differential gene expression screen method, we isolated a gene that is down-regulated in the uterus during pregnancy. This gene encodes the previously identified androgen-regulated protein known as the kidney androgen-regulated protein (KAP) because of its abundant expression in the kidney. Our results showed a high level of KAP messenger RNA (mRNA) in the uteri of nonpregnant rats at all stages of the estrous cycle. We observed that in the pregnant animals, the level of KAP mRNA remained high immediately after fertilization (days 1 and 2), but declined sharply with the progression of pregnancy, falling to almost undetectable levels during midgestation (days 10-15). Interestingly, the level of KAP mRNA started to rise again toward the end (day 19 onward) of pregnancy and was high during parturition. The temporal pattern of expression of KAP in the uterus closely overlapped with the profile of plasma estrogen during pregnancy. Known antagonists of estrogen, such as tamoxifen and ICI 182,780, strongly inhibited uterine KAP gene expression during the estrous cycle and pregnancy, supporting a regulatory role of estrogen in this process. Consistent with this observation, administration of estrogen to ovariectomized animals markedly stimulated (∼10-fold) the level of KAP mRNA in the uterus. Treatment of these animals with progesterone, on the other hand, did not significantly alter KAP gene expression. Immunocytochemical analyses of uterine sections with an antibody against KAP exhibited specific staining in both luminal and glandular epithelia and in myometrium. These uterine locations also possess abundant estrogen receptors and are known targets of estrogen action. Our studies, therefore, revealed that KAP is a useful marker of estrogen action in the uterus, especially during the reproductive cycle and termination of gestation.