Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption–induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.

中文翻译：

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单细胞转录组学和染色质可及性分析阐明了盐皮质激素受体拮抗剂的肾脏保护机制

盐皮质激素过量通常会导致高血压 (HTN) 和肾脏疾病。在我们的研究中，我们使用单细胞表达和染色质可及性工具来表征盐皮质激素靶基因和细胞类型。我们证明，盐皮质激素的作用是通过开放染色质和靶基因表达建立的，主要是在主肾小管和连接肾小管细胞中，在较小程度上是在远曲小管细胞的片段中。我们在醋酸脱氧皮质酮、单侧肾切除术和高盐摄入诱发的高血压和心肾损伤的大鼠模型中，研究了类固醇和非类固醇盐皮质激素拮抗剂（MRA）以及阿米洛利（一种上皮钠通道抑制剂）的肾脏保护作用。损害。所有抗高血压疗法都能防止心肾损伤。然而，finerenone 在减少白蛋白尿和改善足细胞和近端小管细胞的基因表达变化方面特别有效，甚至可以同等程度地降低血压。我们注意到表达分泌性磷酸蛋白 1 ( Spp1 )、Il34和血小板衍生生长因子亚基 b ( Pdgfb ) 的受损/促纤维化肾小管细胞的积累与大鼠肾脏纤维化程度之间存在很强的相关性。该基因特征还显示出对人类肾脏样本进行分类的潜力。我们的多组学方法为 HTN 相关肾病的可能机制、靶细胞类型、类固醇和非类固醇 MRA 以及阿米洛利的保护作用提供了新的见解。