Molecular and Cellular Endocrinology 176 (2001) 155 – 162 Immature ovaries and polycystic kidneys in the congenital polycystic kidney mouse may be due to abnormal sex steroid metabolism David Woo a , Gloria Y. Lee b , Everett Anderson b , Nazneen Aziz c, * a Department of Medicine, Uniersity of California, Los Angeles, CA90095, USA b Department of Cell Biology, Harard Medical School, Boston, MA02115, USA c Harard Medical School, Childrens Hospital, Boston, MA02115, USA Received 6 September 2000; accepted 14 September 2000 Abstract Ke 6 is a 17-hydroxysteroid dehydrogenase (17HSD) that is expressed in the kidneys and gonads. The expression of this gene is markedly reduced in three murine models of recessive polycystic kidney disease, a developmental disorder, where some nephrons within the affected kidneys develop into huge fluid-filled cysts while the non-cystic nephrons atrophies by apoptosis. Here, we show that in the cpk /cpk mouse, which have polycystic kidneys, the female reproductive organs also fail to mature properly and remain arrested at an early stage of development. Direct measurement of 17HSD activity showed a severe reduction in estrogen and androgen metabolism within gonadal and non-gonadal tissues of the cpk /cpk mouse. Using immunofluorescent staining we localized the expression of the Ke 6 protein within the female mouse reproductive organs. Our findings suggest that estrogen/an- drogen metabolism may play an important role in the development of the urogenital systems. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hydroxysteroid dehydrogenase; Polycystic; cpk /cpk mouse; Ke 6; Development; Gonada www.elsevier.com/locate/mce 1. Introduction Ke 6 is a newly identified 17-hydroxysteroid dehy- drogenase (17HSD) (Fomitcheva et al., 1998). The Ke 6 gene is expressed in a number of tissues, both gonadal and non-gonadal (Fomitcheva et al., 1998; Aziz et al., 1993). It is expressed at a very high level in the kidney and liver (Aziz et al., 1993) and is expressed at a moderately high level in the reproductive organs (Fomitcheva et al., 1998). The Ke 6 enzyme can oxidize estradiol, testosterone, and dihydrotestosterone and thereby convert these potent hormones into their weaker metabolites (Fomitcheva et al., 1998). It has the strongest affinity and highest activity for the oxidation of estradiol (Fomitcheva et al., 1998). The Ke 6 enzyme can also reduce estrone into the potent form of estro- gen, estradiol (Fomitcheva et al., 1998). Estrogens and androgens are biologically active as 17-hydroxys- teroids because of higher binding affinity to their recep- tors than 17-keto steroids. Therefore, this class of enzymes play an important role in regulating the level of transcriptional effectors (steroid hormones), which act via nuclear receptors (steroid hormone receptors) in controlling a variety of growth, differentiation, and developmental processes by activating or repressing target genes (steroid hormone regulatory genes). In earlier reports, we had shown that the expression of the Ke 6 gene is severely down-regulated in three murine models of recessive polycystic kidney disease (PKD), the congential polycystic kidney, jck and pcy homozygote mice (Aziz et al., 1993; Maxwell et al., 1995). We had also shown that the expression of the Ke 6 protein is absent from the epithelia lining the cysts in the cpk /cpk mouse kidney (Aziz et al., 1996a). Impor- tantly, when we used antisense oligodeoxynucleotides in an organ culture system to achieve targeted inhibition * Corresponding author. Present address: Interleukin Genetics, 135 Beaver Road, Waltham, MA 02452. Tel.: +781-398-0718. E-mail address: naziz@ilgenetics.com (N. Aziz). 0303-7207/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0303-7207(00)00398-1