Olivier Staub, Anne Debonneville, Matteo Stifanelli, Alexandria Juffre, Marc P Maillard, Michelle L Gumz, Lama Al-Qusairi
{"title":"肾小管SGK1是实现血压飙升和昼夜节律所必需的。","authors":"Olivier Staub, Anne Debonneville, Matteo Stifanelli, Alexandria Juffre, Marc P Maillard, Michelle L Gumz, Lama Al-Qusairi","doi":"10.1152/ajprenal.00211.2023","DOIUrl":null,"url":null,"abstract":"<p><p>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 (<i>SGK1</i>), 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 <i>SGK1</i> in BP circadian regulation has not yet been demonstrated. Using telemetry, we analyzed BP in the inducible renal tubule-specific <i>Sgk1<sup>Pax8/LC1</sup></i> model under basal K<sup>+</sup> diet (1% K<sup>+</sup>) and high-K<sup>+</sup> diet (HKD; 5% K<sup>+</sup>). Our data revealed that, under basal conditions, renal <i>SGK1</i> plays a minor role in BP regulation; however, after 1 wk of HKD, <i>Sgk1<sup>Pax8/LC1</sup></i> 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), <i>Sgk1</i><sup>Pax8/LC1</sup> 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 <i>1</i>) the kidney plays a significant role in setting the BP circadian rhythm; <i>2</i>) renal tubule <i>SGK1</i> mediates the BP surge and, thus, the day/night BP difference; <i>3</i>) long-term renal <i>SGK1</i> deletion results in lower BP in mutant compared with control mice; and <i>4</i>) renal <i>SGK1</i> indirectly regulates pulse pressure due to compensatory alterations in aldosterone levels.<b>NEW & NOTEWORTHY</b> 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 (<i>SGK1</i>) 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 <i>SGK1</i> function to avoid dysregulation of BP circadian rhythm.</p>","PeriodicalId":7588,"journal":{"name":"American Journal of Physiology-renal Physiology","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10878722/pdf/","citationCount":"0","resultStr":"{\"title\":\"Renal tubular SGK1 is required to achieve blood pressure surge and circadian rhythm.\",\"authors\":\"Olivier Staub, Anne Debonneville, Matteo Stifanelli, Alexandria Juffre, Marc P Maillard, Michelle L Gumz, Lama Al-Qusairi\",\"doi\":\"10.1152/ajprenal.00211.2023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 (<i>SGK1</i>), 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 <i>SGK1</i> in BP circadian regulation has not yet been demonstrated. Using telemetry, we analyzed BP in the inducible renal tubule-specific <i>Sgk1<sup>Pax8/LC1</sup></i> model under basal K<sup>+</sup> diet (1% K<sup>+</sup>) and high-K<sup>+</sup> diet (HKD; 5% K<sup>+</sup>). Our data revealed that, under basal conditions, renal <i>SGK1</i> plays a minor role in BP regulation; however, after 1 wk of HKD, <i>Sgk1<sup>Pax8/LC1</sup></i> 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), <i>Sgk1</i><sup>Pax8/LC1</sup> 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 <i>1</i>) the kidney plays a significant role in setting the BP circadian rhythm; <i>2</i>) renal tubule <i>SGK1</i> mediates the BP surge and, thus, the day/night BP difference; <i>3</i>) long-term renal <i>SGK1</i> deletion results in lower BP in mutant compared with control mice; and <i>4</i>) renal <i>SGK1</i> indirectly regulates pulse pressure due to compensatory alterations in aldosterone levels.<b>NEW & NOTEWORTHY</b> 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 (<i>SGK1</i>) 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 <i>SGK1</i> function to avoid dysregulation of BP circadian rhythm.</p>\",\"PeriodicalId\":7588,\"journal\":{\"name\":\"American Journal of Physiology-renal Physiology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2023-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10878722/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American Journal of Physiology-renal Physiology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1152/ajprenal.00211.2023\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/9/7 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"PHYSIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Physiology-renal Physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajprenal.00211.2023","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/9/7 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
Renal tubular SGK1 is required to achieve blood pressure surge and circadian rhythm.
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.
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.