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The Human Kidney Is a Progesterone-Metabolizing and Androgen-Producing Organ

Department of Endocrinology, Klinikum Benjamin Franklin, Free University, 12200 Berlin, Germany

Address all correspondence and requests for reprints to: Dr. Marcus Quinkler, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail: m.o.quinkler{at}bham.ac.uk.

Progesterone (P) is a potent antagonist of the human mineralocorticoid receptor (MR) in vitro. We have previously demonstrated effective downstream metabolism of P in the kidney. This mechanism potentially protects the MR from P action. Here, we have investigated the expression and functional activity of steroidogenic enzymes in human kidney. RT-PCR analysis demonstrated the expression of 5-reductase type 1, 5ß-reductase, aldo-keto-reductase (AKR) 1C1, AKR1C2, AKR1C3, 3ß-hydroxysteroid dehydrogenase (3ß-HSD) type 2, and 17-hydroxylase/17,20-lyase (P450c17). The presence of 3ß-HSD type 2 and P450c17 indicated that conversion of pregnenolone to dehydroepiandrosterone (DHEA) and to androstenedione may take place effectively in kidney. To investigate this further, we incubated kidney subcellular fractions with radiolabeled pregnenolone. This resulted in efficient formation of DHEA from pregnenolone, indicating both 17-hydroxylase and 17,20-lyase activities exerted by P450c17. Radiolabeled DHEA was converted via androstenedione, androstenediol, and testosterone, indicating both 3ß-HSD type 2 activity and 17ß-HSD activity. In addition, the conversion of testosterone to 5-dihydrotestosterone was detectable, indicating 5-reductase activity. In conclusion, we verified the expression and functional activity of several enzymes involved in downstream metabolism of P and androgen synthesis in human kidney. These findings may be critical to the understanding of water balance during the menstrual cycle and pregnancy and of sex differences in hypertension.

This work was supported by Research Grant DI 741/1-3 from the Deutsche Forschungsgemeinschaft (to S.D.) and Deutsche Forschungsgemeinschaft Postdoctoral Research Fellowship Grant QU142/1-1 (to M.Q.).

Abbreviations: AKR, Aldo-keto-reductase; 20-DH-P, 20-dihydroprogesterone; DHEA, dehydroepiandrosterone; DH-T, dihydrotestosterone; 3-diol, 3-androstanediol; 4-dione, androstenedione; 3ß-HSD, 3ß-hydroxysteroid dehydrogenase; MR, mineralocorticoid receptor; 17-OH-P, 17-hydroxyprogesterone; 17-OH-Preg, 17-hydroxypregnenolone; P, progesterone; P450c17, 17-hydroxylase/17,20-lyase; Preg, pregnenolone; T, testosterone; 3ß,5-TH-P, 5-pregnan-3ß-ol-20-one; TLC, thin layer chromatography; V_max, maximal reaction velocity.

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