Renal tubular SGK1 is required to achieve blood pressure surge and circadian rhythm.

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-11-01 Epub Date: 2023-09-07 DOI:10.1152/ajprenal.00211.2023
Olivier Staub, Anne Debonneville, Matteo Stifanelli, Alexandria Juffre, Marc P Maillard, Michelle L Gumz, Lama Al-Qusairi
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Abstract

Blood pressure (BP) follows a circadian pattern that rises during the active phase of the day (morning surge) and decreases during the inactive (night dipping) phase of the day. The morning surge coincides with increased circulating glucocorticoids and aldosterone, ligands for glucocorticoid receptors and mineralocorticoid receptors, respectively. Serum- and glucocorticoid-induced kinase 1 (SGK1), a clock-controlled and glucocorticoid receptor- and mineralocorticoid receptor-induced gene, plays a role in BP regulation in human and animal models. However, the role of SGK1 in BP circadian regulation has not yet been demonstrated. Using telemetry, we analyzed BP in the inducible renal tubule-specific Sgk1Pax8/LC1 model under basal K+ diet (1% K+) and high-K+ diet (HKD; 5% K+). Our data revealed that, under basal conditions, renal SGK1 plays a minor role in BP regulation; however, after 1 wk of HKD, Sgk1Pax8/LC1 mice exhibited significant defects in diastolic BP (DBP), including a blunted surge, a decreased amplitude, and reduced day/night differences. After prolonged HKD (7 wk), Sgk1Pax8/LC1 mice had lower BP than control mice and exhibited reduced DBP amplitude, together with decreased DBP day/night differences and midline estimating statistic of rhythm (MESOR). Interestingly, renal SGK1 deletion increased pulse pressure, likely secondary to an increase in circulating aldosterone. Taken together, our data suggest that 1) the kidney plays a significant role in setting the BP circadian rhythm; 2) renal tubule SGK1 mediates the BP surge and, thus, the day/night BP difference; 3) long-term renal SGK1 deletion results in lower BP in mutant compared with control mice; and 4) renal SGK1 indirectly regulates pulse pressure due to compensatory alterations in aldosterone levels.NEW & NOTEWORTHY Dysregulation of blood pressure (BP) circadian rhythm is associated with metabolic, cardiovascular, and kidney diseases. Our study provides experimental evidence demonstrating, for the first time, that renal tubule serum- and glucocorticoid-induced kinase 1 (SGK1) plays an essential role in inducing the BP surge. Inhibitors and activators of SGK1 signaling are parts of several therapeutic strategies. Our findings highlight the importance of the drug intake timing to be in phase with SGK1 function to avoid dysregulation of BP circadian rhythm.

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肾小管SGK1是实现血压飙升和昼夜节律所必需的。
血压(BP)遵循昼夜节律模式,在一天中的活跃阶段(早晨激增)升高,在一日中的非活跃阶段(夜间下降)降低。早晨的激增与循环中糖皮质激素和醛固酮的增加相吻合,这两种激素分别是糖皮质激素受体和盐皮质激素受体的配体。血清和糖皮质激素诱导激酶1(SGK1)是一种时钟控制的糖皮质激素受体和盐皮质激素受体诱导的基因,在人类和动物模型中的BP调节中发挥作用。然而,SGK1在BP昼夜节律调节中的作用尚未得到证实。使用遥测技术,我们分析了基础K+饮食(1%K+)和高K+食物(HKD;5%K+)下诱导型肾小管特异性Sgk1Pax8/LC1模型中的BP。我们的数据显示,在基础条件下,肾脏SGK1在BP调节中起次要作用;然而,在HKD 1周后,Sgk1Pax8/LC1小鼠表现出舒张压(DBP)的显著缺陷,包括激增减弱、振幅降低和昼夜差异减少。在延长HKD(7周)后,Sgk1Pax8/LC1小鼠的血压低于对照小鼠,并表现出DBP幅度降低,同时DBP昼夜差异和节律中线估计统计(MESOR)降低。有趣的是,肾脏SGK1缺失增加了脉压,这可能是循环醛固酮增加的继发因素。总之,我们的数据表明:1)肾脏在设定血压昼夜节律方面发挥着重要作用;2) 肾小管SGK1介导血压激增,从而介导昼夜血压差异;3) 与对照小鼠相比,长期肾脏SGK1缺失导致突变体中的BP较低;和4)肾SGK1由于醛固酮水平的代偿性改变而间接调节脉压。新的和值得注意的血压昼夜节律失调与代谢、心血管和肾脏疾病有关。我们的研究首次提供了实验证据,证明肾小管血清和糖皮质激素诱导的激酶1(SGK1)在诱导血压飙升中起着重要作用。SGK1信号传导的抑制剂和激活剂是几种治疗策略的一部分。我们的研究结果强调了药物摄入时间与SGK1功能同相的重要性,以避免BP昼夜节律失调。
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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
期刊最新文献
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