Dumeige Laurence, Storey Caroline, Decourtye Lyvianne, Nehlich Melanie, Lhadj Christophe, Viengchareun Say, Kappeler Laurent, Lombès Marc, Martinerie Laetitia
Inserm U1185, Univ Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France.
Service d'Endocrinologie Pédiatrique, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, F-75019 Paris, France.
Int J Mol Sci. 2017 Feb 21;18(2):457. doi: 10.3390/ijms18020457.
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 () and glucocorticoid-induced leucine zipper protein (), together with , Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for 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.
在包括高血压在内的各种生物学过程中已发现性别差异。盐皮质激素信号通路是早期动脉高血压的一个重要促成因素，然而其性别特异性表达鲜有研究，尤其是在肾脏方面。测量成年雄性和雌性小鼠的基础收缩压（SBP）和心率（HR）。使用逆转录定量PCR（RT-qPCR）在雄性和雌性小鼠的不同发育阶段对盐皮质激素信号主要参与者进行肾脏基因表达研究，并将其与肺中相同基因的表达进行比较，肺是另一个调节离子交换和电解质平衡的盐皮质激素上皮靶组织。还在分化的KC3AC1肾细胞中研究了性激素对这些基因的调节作用。此外，通过免疫印迹法测量盐皮质激素特异性调节剂2型11β-羟基类固醇脱氢酶（11βHSD2）蛋白的肾脏表达，并使用液相色谱串联质谱（LC-MSMS）方法间接评估其在血浆中的活性。发现雌性的SBP和HR显著低于雄性。这伴随着盐皮质激素靶基因血清和糖皮质激素调节激酶1（）以及糖皮质激素诱导的亮氨酸拉链蛋白（）在整个肾脏发育过程中的性别和组织特异性表达谱，以及。最后，在体外证明了性激素在这种性别特异性表达谱中的作用，最显著的是对mRNA表达的影响。我们证明了盐皮质激素途径的组织特异性、性别依赖性和发育调节性表达模式，这可能在生理学和病理学中具有重要意义。
