Gertrude Arthur, Audrey Poupeau, Katherine Biel, Jeffrey L Osborn, Ming Gong, Terry D Hinds, Volkhard Lindner, Analia S Loria
{"title":"Human soluble prorenin receptor expressed in mouse renal collecting duct shows sex-specific effect on cardiorenal function.","authors":"Gertrude Arthur, Audrey Poupeau, Katherine Biel, Jeffrey L Osborn, Ming Gong, Terry D Hinds, Volkhard Lindner, Analia S Loria","doi":"10.1152/ajprenal.00375.2023","DOIUrl":null,"url":null,"abstract":"<p><p>Soluble prorenin receptor (sPRR), a component of the renin-angiotensin system (RAS), has been identified as a plasma biomarker for hypertension and cardiovascular diseases in humans. Despite studies showing that sPRR in the kidney is produced by tubular cells in the renal collecting duct (CD), its biological actions modulating cardiorenal function in physiological conditions remain unknown. Therefore, the objective of our study was to investigate whether CD-derived human sPRR (HsPRR) expression influences cardiorenal function and examine sex and circadian differences. Thus, we investigated the status of the intrarenal RAS, water and electrolyte balance, renal filtration capacity, and blood pressure (BP) regulation in CD-HsPRR and control (CTL) mice. CD-HsPRR mice were generated by breeding human sPRR-Myc-tag mice with Hoxb7/Cre mice. Renal sPRR expression increased in CD-HsPRR mice, but circulating sPRR and RAS levels were unchanged compared with CTL mice. Only female littermates expressing CD-HsPRR showed <i>1</i>) increased 24-h BP, <i>2</i>) an impaired BP response to an acute dose of losartan and attenuated angiotensin II (ANG II)-induced hypertension, <i>3</i>) reduced angiotensin-converting enzyme activity and ANG II content in the renal cortex, and <i>4</i>) decreased glomerular filtration rate, with no changes in natriuresis and kaliuresis despite upregulation of the β-subunit of the epithelial Na<sup>+</sup> channel in the renal cortex. These cardiorenal alterations were displayed only during the active phase of the day. Taken together, these data suggest that HsPRR could interact with ANG II type 1 receptors mediating sex-specific, ANG II-independent renal dysfunction and a prohypertensive phenotype in a sex-specific manner.<b>NEW & NOTEWORTHY</b> We successfully generated a humanized mouse model that expresses human sPRR in the collecting duct. Collecting duct-derived human sPRR did not change circulating sPRR and RAS levels but increased daytime BP in female mice while showing an attenuated angiotensin II-dependent pressor response. These findings may aid in elucidating the mechanisms by which women show uncontrolled BP in response to antihypertensive treatments targeting the RAS, improving approaches to reduce uncontrolled BP and chronic kidney disease incidences in women.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208026/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Renal physiology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1152/ajprenal.00375.2023","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/22 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Soluble prorenin receptor (sPRR), a component of the renin-angiotensin system (RAS), has been identified as a plasma biomarker for hypertension and cardiovascular diseases in humans. Despite studies showing that sPRR in the kidney is produced by tubular cells in the renal collecting duct (CD), its biological actions modulating cardiorenal function in physiological conditions remain unknown. Therefore, the objective of our study was to investigate whether CD-derived human sPRR (HsPRR) expression influences cardiorenal function and examine sex and circadian differences. Thus, we investigated the status of the intrarenal RAS, water and electrolyte balance, renal filtration capacity, and blood pressure (BP) regulation in CD-HsPRR and control (CTL) mice. CD-HsPRR mice were generated by breeding human sPRR-Myc-tag mice with Hoxb7/Cre mice. Renal sPRR expression increased in CD-HsPRR mice, but circulating sPRR and RAS levels were unchanged compared with CTL mice. Only female littermates expressing CD-HsPRR showed 1) increased 24-h BP, 2) an impaired BP response to an acute dose of losartan and attenuated angiotensin II (ANG II)-induced hypertension, 3) reduced angiotensin-converting enzyme activity and ANG II content in the renal cortex, and 4) decreased glomerular filtration rate, with no changes in natriuresis and kaliuresis despite upregulation of the β-subunit of the epithelial Na+ channel in the renal cortex. These cardiorenal alterations were displayed only during the active phase of the day. Taken together, these data suggest that HsPRR could interact with ANG II type 1 receptors mediating sex-specific, ANG II-independent renal dysfunction and a prohypertensive phenotype in a sex-specific manner.NEW & NOTEWORTHY We successfully generated a humanized mouse model that expresses human sPRR in the collecting duct. Collecting duct-derived human sPRR did not change circulating sPRR and RAS levels but increased daytime BP in female mice while showing an attenuated angiotensin II-dependent pressor response. These findings may aid in elucidating the mechanisms by which women show uncontrolled BP in response to antihypertensive treatments targeting the RAS, improving approaches to reduce uncontrolled BP and chronic kidney disease incidences in women.
可溶性肾素受体(sPRR)是肾素血管紧张素系统(RAS)的一个组成部分,已被确定为人类高血压和心血管疾病的血浆生物标志物。尽管研究表明肾脏中的 sPRR 由肾集合管(CD)肾小管细胞产生,但其调节心肾功能的生物学作用仍然未知。因此,本研究旨在创建一种新的小鼠模型,研究在CD中表达人sPRR(HsPRR)如何影响以普通饲料喂养的雌雄小鼠的肾内RAS状态和肾血流动力学。CD-HsPRR小鼠由表达Hoxb7/Cre的人sPRR-Myc-tag转基因小鼠与表达Hoxb7/Cre的转基因小鼠杂交产生,与CTL小鼠相比,CD-HsPRR小鼠的雌雄肾脏sPRR表达量增加,但循环水平不变。血浆中的 RAS 水平也不受 CD 中 HsPRR 表达的影响。CD-HsPRR 的表达仅在雌性同窝鼠中显示:1)由于日间平均值和收缩压值升高,24 小时血压升高;2)对急性剂量洛沙坦的血压反应受损,慢性血管紧张素 II(AngII)-高血压降低;3)肾皮质中 ACE 活性和 Ang II 含量降低;4)尽管肾皮质中 β-ENaC 上调,但肾小球滤过率(GFR)降低,利尿和利尿功能无变化。总之,这些数据表明,HsPRR 在 CD 中的表达可与 Ang II 1 型受体相互作用,介导一种性别特异性、不依赖于 Ang II 的肾功能障碍和促高血压表型。