Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

Abstract

Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS) method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1) and glucocorticoid-induced leucine zipper protein (Gilz), together with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology.

Effects of chronically high levels of aldosterone on different cognitive dimensions: an investigation in patients with primary aldosteronism

“…These contrasting findings could be due to different underlying mechanisms associated with chronic exposure to aldosterone versus acute blockade with a MR antagonist. Sex differences in memory functions related to MR function have been described in animal data (50) and sexually dimorphic regulation of the MR- and gender-specific effects of aldosterone are at least described for other tissues (51, 52).…”

Sexual Dimorphism of Corticosteroid Signaling during Kidney Development

“…Whether the regulatory mechanisms implicated in MR and GR expression, or their coregulators expression, could contribute to the emergence of a sexual dimorphism remain to be explored. Finally, to the best our knowledge, only one study has reported a sexual dimorphism for corticosteroid receptors expression in the kidney [ 77 ].…”

“…Sex steroids are known to influence the activity of the RAS in adults: testosterone promotes the action of Ang II via AT1R, whereas estrogen decreases the AT1R/AT2R ratio inducing a different receptivity to Ang II [ 103 ]. Our group observed a sex and organ-specific regulation of target genes of the corticosteroid signaling pathway in adult mice, along with a higher expression of renal 11βHSD2 in female mice, promoting the selectivity of aldosterone for its receptor [ 77 ]. This increased activation of the mineralocorticoid pathway in females does not increase blood pressure but could be aimed at a finer regulation of potassium excretion by distal tubules, which is an adaptive mechanism optimized for maternal–fetal homeostasis during pregnancy [ 106 ].…”

“…Data in the developing fetus and newborn are less extensive. While no difference in CYP11B1 and CYP11B2 gene expressions or steroid concentrations of aldosterone and cortisol/corticosterone has been reported between male and female fetuses during development or at birth, sex specific MR and 11βHSD2 expression have been demonstrated [ 77 ]. Our group reported a sexual dimorphism in renal expression of the MR and its target genes during the perinatal period, with a peak in MR, GR, and mRNA expression of target genes at 17.5 days of gestation in female mice but not in males.…”

Preterm birth is associated with epigenetic programming of transgenerational hypertension in mice

“…Systolic blood pressure (SBP) measurements were conducted in the animal facility of the FRIM (Fédération de Recherche en Imagerie Multi-Modalité, Paris-Diderot University, France) by tail-cuff plethysmography in trained and nonanesthetized animals as previously described 18 . Briefly, animals were acclimatized for at least 5 days before SBP measurements.…”