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 5α-reductase type 1, 5β-reductase, aldo-keto-reductase (AKR) 1C1, AKR1C2, AKR1C3, 3β-hydroxysteroid dehydrogenase (3β-HSD) type 2, and 17α-hydroxylase/17,20-lyase (P450c17). The presence of 3β-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 17α-hydroxylase and 17,20-lyase activities exerted by P450c17. Radiolabeled DHEA was converted via androstenedione, androstenediol, and testosterone, indicating both 3β-HSD type 2 activity and 17β-HSD activity. In addition, the conversion of testosterone to 5α-dihydrotestosterone was detectable, indicating 5α-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.
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The Journal of Clinical Endocrinology & Metabolism, Volume 88, Issue 6, 1 June 2003, Pages 2803–2809, https://doi.org/10.1210/jc.2002-021970
01 June 2003