Aldosterone, the main mineralocorticoid hormone in humans, plays a pivotal role in the control of water and salt reabsorption via activation of the mineralocorticoid receptor (MR). Alterations in MR signaling pathway lead to renal dysfunction, including chronic kidney disease and renal fibrosis, that can be prevented or treated with mineralocorticoid receptor antagonists (MRAs). Here, we used RNA-Sequencing to analyze effects of two MRAs, spironolactone and finerenone, on the aldosterone-induced transcriptome of a human renal cell line stably expressing the MR. Bioinformatics analysis of the data set reveals the identity of hundreds of genes induced or repressed by aldosterone. Their regulation is modulated in a time-dependent manner and, for the induced genes, depends on the aldosterone-driven direct binding of the MR onto its genomic targets that we have previously characterized. Although both MRAs block aldosterone-induced as well as aldosterone-repressed genes qualitatively similarly, finerenone has a quantitatively more efficient antagonism on some aldosterone-induced genes. Our data provide the first complete transcriptome for aldosterone on a human renal cell line and identifies pro-inflammatory markers (IL6, IL11, CCL7, and CXCL8) as aldosterone-repressed genes.

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Finerenone和螺内酯对人肾细胞醛固酮调节转录组的拮抗作用

醛固酮是人类的主要盐皮质激素，通过激活盐皮质激素受体 (MR) 在控制水和盐重吸收方面发挥着关键作用。MR 信号通路的改变会导致肾功能障碍，包括慢性肾病和肾纤维化，这可以用盐皮质激素受体拮抗剂 (MRA) 来预防或治疗。在这里，我们使用 RNA 测序来分析两种 MRA，螺内酯和 Finerenone，对稳定表达 MR 的人肾细胞系的醛固酮诱导的转录组的影响。数据集的生物信息学分析揭示了由醛固酮诱导或抑制的数百个基因的身份。它们的调节以时间依赖性方式进行调节，对于诱导基因，依赖于醛固酮驱动的 MR 与其基因组靶标的直接结合，我们之前已经表征了这一点。尽管这两种 MRA 阻断醛固酮诱导和醛固酮抑制基因的质量相似，但 Finerenone 对某些醛固酮诱导基因具有数量上更有效的拮抗作用。我们的数据提供了人类肾细胞系上醛固酮的第一个完整转录组，并将促炎标志物（IL6、IL11、CCL7 和 CXCL8）鉴定为醛固酮抑制基因。