Characterization of Ke 6, a New 17β-Hydroxysteroid Dehydrogenase, and Its Expression in Gonadal Tissues

Julia Fomitcheva,Michael E Baker,Everett Anderson,Gloria Y Lee,Nazneen Aziz

doi:10.1074/jbc.273.35.22664

Julia Fomitcheva, Michael E Baker + Show 3 more

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https://doi.org/10.1074/jbc.273.35.22664

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Abstract

The abnormal regulation of the Ke 6 gene has been linked to the development of recessive polycystic kidney disease in the mouse. In this report, we have shown that Ke 6 is a 17beta-hydroxysteroid dehydrogenase and can regulate the concentration of biologically active estrogens and androgens. The Ke 6 enzyme is preferentially an oxidative enzyme and inactivates estradiol, testosterone, and dihydrotestosterone. However, the enzyme has some reductive activity and can synthesize estradiol from estrone. We find that the Ke 6 gene is expressed within the ovaries and testes. The presence of Ke 6 protein within the cumulus cells surrounding the oocyte places it in a strategic location to control the level of steroids to which the egg is exposed. Previously, it had been shown that glucocorticoids can induce renal cysts in the neonatal rodent, only when given at a narrow time window of postnatal kidney development. We propose that the reduction in the level of Ke 6 enzyme, which occurs in the cpk, jck, and pcy mice, may lead to abnormal elevations in local level of sex steroids, which either directly or indirectly via abnormal glucocorticoid metabolism result in recessive renal cystic disease, a developmental disorder of the kidney.

Highlights

The Ke 6 gene, encoded within the major histocompatibility complex, has been intimately linked to the development of cysts in the kidney and liver of mice [1,2,3,4,5,6]
We propose that the reduction in the level of Ke 6 enzyme, which occurs in the cpk, jck, and pcy mice, may lead to abnormal elevations in local level of sex steroids, which either directly or indirectly via abnormal glucocorticoid metabolism result in recessive renal cystic disease, a developmental disorder of the kidney
The identification of the substrate of Ke 6 allows us to postulate that regulated sex steroid metabolism plays a crucial role in the development of the mammalian kidney, and aberrations in this regulation leads to developmental problems

Summary

Introduction

The Ke 6 gene, encoded within the major histocompatibility complex, has been intimately linked to the development of cysts in the kidney and liver of mice [1,2,3,4,5,6]. We searched the data base again with Ke 6 and found it is similar to 17␤HSD4 [9] This prompted us to examine Ke 6 for 17␤HSD activity with various androgen and estrogen substrates. We propose that the developing kidney is affected by abnormal estrogen/androgen metabolism or by abnormal glucocorticoid metabolism, which could occur as a consequence of elevated sex steroid levels. Estrogen levels have been implicated in the inhibition of 11␤HSD enzyme in a study by Low et al [10], where it was determined that gonadectomy of the normal female mouse stimulated the expression of the 11␤HSD1 gene and estradiol replacement inhibited its activity. We have localized the expression of Ke 6 within the rat ovary These findings support a function of Ke 6 as a 17␤HSD, a regulator of sex steroid concentrations in these tissues

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