Expression of the progesterone receptor and progesterone-metabolising enzymes in the female and male human kidney

Abstract

Due to high binding affinity of progesterone to the human mineralocorticoid receptor (hMR), progesterone competes with the natural ligand aldosterone. In order to analyse how homeostasis can be maintained by mineralocorticoid function of aldosterone at the MR, especially in the presence of elevated progesterone concentrations during the luteal phase and pregnancy, we investigated protective mechanisms such as the decrease of free progesterone by additional binding sites and progesterone metabolism in renal cells. As a prerequisite for sequestration of progesterone by binding to the human progesterone receptor (hPR) we demonstrated the existence of hPR expression in female and male kidney cortex and medulla at the level of transcription and translation. We identified hPR RNA by sequencing the RT-PCR product and characterised the receptor by ligand binding and Scatchard plot analysis. The localisation of renal hPR was shown predominantly in individual epithelial cells of distal tubules by immunohistology, and the isoform hPR-B was detected by Western blot analysis. As a precondition for renal progesterone metabolism, we investigated the expression of steroid-metabolising enzymes for conversion of progesterone to metabolites with lower affinity to the hMR. We identified the enzyme 17α-hydroxylase for renal 17α,-hydroxylation of progesterone. For 20α-reduction, different hydroxysteroid dehydrogenases (HSDs) such as 20α,-HSD, 17β-HSD type 5 (3α,-HSD type 2) and 3α,-HSD type 3 were found. Further, we detected the expression of 3β-HSD type 2 for 3β-reduction, 5α-reductase (Red) type 1 for 5α-reduction, and 5β-Red for 5β-reduction of progesterone in the human kidney. Therefore metabolism of progesterone and/or binding to hPR could reduce competition with aldosterone at the MR and enable the mineralocorticoid function.