收集管源性肾素受体参与小鼠2肾、1夹诱导的缺血性肾病和肾血管性高血压

IF 3.4
Ziwei Fu, Kannaree Kaewsaro, Sunhapas Soodvilai, Alex Kimball, Tianxin Yang
{"title":"收集管源性肾素受体参与小鼠2肾、1夹诱导的缺血性肾病和肾血管性高血压","authors":"Ziwei Fu, Kannaree Kaewsaro, Sunhapas Soodvilai, Alex Kimball, Tianxin Yang","doi":"10.1152/ajprenal.00340.2024","DOIUrl":null,"url":null,"abstract":"<p><p>The 2-kidney, 1-clip (2K1C) Goldblatt model features overactivation of the systemic renin-angiotensin system (RAS) due to increased renin release from juxtaglomerular cells. However, no previous study has functionally assessed the potential involvement of the intrarenal RAS in this model. Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), where it plays a key role in regulating the intrarenal RAS under physiopathological conditions. In the present study, we used a mouse model of CD-specific deletion of PRR (CD PRR KO) to examine the role of CD PRR in the pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy and to further explore the underlying mechanism. Floxed and CD PRR KO mice underwent either a sham operation or clipping the left renal artery using a polyurethane cuff with an internal diameter of ∼2.7 mm for 1 mo. Subsequent analyses included blood pressure measurement, renal injury assessment, examination of epithelial Na<sup>+</sup> channel (ENaC) subunit expression, and evaluation of plasma and intrarenal renin and angiotensin II levels. Clipping-induced hypertension and renal injury were both attenuated in CD PRR KO mice as compared with floxed controls. The protective phenotype of the null mice was paralleled with suppressed intrarenal renin levels. Moreover, renal medullary α-ENaC mRNA and protein expression were elevated by clipping in floxed mice, which was blunted in CD PRR KO mice. Together, these results suggest that the activation of CD PRR stimulates components of the intrarenal RAS and renal medullary α-ENaC, which result in increased tubular sodium reabsorption and thus contribute to 2K1C-induced renovascular hypertension and ischemic nephropathy.<b>NEW & NOTEWORTHY</b> Nonspecifically targeting the RAS in renovascular hypertension and ischemic nephropathy is only partially effective and also limited by class toxicities of hyperkalemia and acute decline of renal function. Our results help understand the CD PRR-mediated local mechanism in the pathogenesis of renovascular hypertension and ischemic nephropathy, and also support CD PRR as a potential therapeutic target for selective inhibition of the intrarenal RAS to treat this devastating disease.</p>","PeriodicalId":93867,"journal":{"name":"American journal of physiology. Renal physiology","volume":" ","pages":"F46-F58"},"PeriodicalIF":3.4000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Collecting duct-derived (pro)renin receptor contributes to 2-kidney, 1-clip-induced ischemic nephropathy and renovascular hypertension in mice.\",\"authors\":\"Ziwei Fu, Kannaree Kaewsaro, Sunhapas Soodvilai, Alex Kimball, Tianxin Yang\",\"doi\":\"10.1152/ajprenal.00340.2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The 2-kidney, 1-clip (2K1C) Goldblatt model features overactivation of the systemic renin-angiotensin system (RAS) due to increased renin release from juxtaglomerular cells. However, no previous study has functionally assessed the potential involvement of the intrarenal RAS in this model. Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), where it plays a key role in regulating the intrarenal RAS under physiopathological conditions. In the present study, we used a mouse model of CD-specific deletion of PRR (CD PRR KO) to examine the role of CD PRR in the pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy and to further explore the underlying mechanism. Floxed and CD PRR KO mice underwent either a sham operation or clipping the left renal artery using a polyurethane cuff with an internal diameter of ∼2.7 mm for 1 mo. Subsequent analyses included blood pressure measurement, renal injury assessment, examination of epithelial Na<sup>+</sup> channel (ENaC) subunit expression, and evaluation of plasma and intrarenal renin and angiotensin II levels. Clipping-induced hypertension and renal injury were both attenuated in CD PRR KO mice as compared with floxed controls. The protective phenotype of the null mice was paralleled with suppressed intrarenal renin levels. Moreover, renal medullary α-ENaC mRNA and protein expression were elevated by clipping in floxed mice, which was blunted in CD PRR KO mice. Together, these results suggest that the activation of CD PRR stimulates components of the intrarenal RAS and renal medullary α-ENaC, which result in increased tubular sodium reabsorption and thus contribute to 2K1C-induced renovascular hypertension and ischemic nephropathy.<b>NEW & NOTEWORTHY</b> Nonspecifically targeting the RAS in renovascular hypertension and ischemic nephropathy is only partially effective and also limited by class toxicities of hyperkalemia and acute decline of renal function. Our results help understand the CD PRR-mediated local mechanism in the pathogenesis of renovascular hypertension and ischemic nephropathy, and also support CD PRR as a potential therapeutic target for selective inhibition of the intrarenal RAS to treat this devastating disease.</p>\",\"PeriodicalId\":93867,\"journal\":{\"name\":\"American journal of physiology. Renal physiology\",\"volume\":\" \",\"pages\":\"F46-F58\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of physiology. Renal physiology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1152/ajprenal.00340.2024\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/5/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Renal physiology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1152/ajprenal.00340.2024","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/5/28 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

2肾1夹(2K1C) Goldblatt模型的特点是,由于肾小球旁细胞肾素释放增加,全体性肾素血管紧张素系统(RAS)过度激活。然而,之前没有研究从功能上评估该模型中可能涉及的肾内RAS。在肾脏内,(原)肾素受体(PRR)主要在集管(CD)中表达,在生理病理条件下参与肾内RAS的调节。本研究采用小鼠CD特异性PRR缺失(CD PRR KO)模型,探讨CD PRR在2k1c诱导的肾血管性高血压和缺血性肾病发病机制中的作用,并进一步探讨其潜在机制。Floxed和CD PRR KO小鼠分别进行假手术或用内径约2.7 mm的聚氨酯袖带夹住左肾动脉一个月。随后的分析包括血压测量、肾损伤评估、ENaC亚基表达检查、血浆和肾内肾素和血管紧张素II水平评估。与固定对照组相比,CD - PRR - KO小鼠剪枝诱导的高血压和肾损伤均减轻。小鼠的保护性表型与肾内肾素水平的抑制是平行的。此外,剪断小鼠的肾髓α-ENaC mRNA和蛋白表达升高,而CD - PRR - KO小鼠的α-ENaC mRNA和蛋白表达减弱。总之,这些结果表明,CD PRR的激活刺激肾内RAS和肾髓α-ENaC的成分,导致小管钠重吸收增加,从而促进2k1c诱导的肾血管性高血压和缺血性肾病。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Collecting duct-derived (pro)renin receptor contributes to 2-kidney, 1-clip-induced ischemic nephropathy and renovascular hypertension in mice.

The 2-kidney, 1-clip (2K1C) Goldblatt model features overactivation of the systemic renin-angiotensin system (RAS) due to increased renin release from juxtaglomerular cells. However, no previous study has functionally assessed the potential involvement of the intrarenal RAS in this model. Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), where it plays a key role in regulating the intrarenal RAS under physiopathological conditions. In the present study, we used a mouse model of CD-specific deletion of PRR (CD PRR KO) to examine the role of CD PRR in the pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy and to further explore the underlying mechanism. Floxed and CD PRR KO mice underwent either a sham operation or clipping the left renal artery using a polyurethane cuff with an internal diameter of ∼2.7 mm for 1 mo. Subsequent analyses included blood pressure measurement, renal injury assessment, examination of epithelial Na+ channel (ENaC) subunit expression, and evaluation of plasma and intrarenal renin and angiotensin II levels. Clipping-induced hypertension and renal injury were both attenuated in CD PRR KO mice as compared with floxed controls. The protective phenotype of the null mice was paralleled with suppressed intrarenal renin levels. Moreover, renal medullary α-ENaC mRNA and protein expression were elevated by clipping in floxed mice, which was blunted in CD PRR KO mice. Together, these results suggest that the activation of CD PRR stimulates components of the intrarenal RAS and renal medullary α-ENaC, which result in increased tubular sodium reabsorption and thus contribute to 2K1C-induced renovascular hypertension and ischemic nephropathy.NEW & NOTEWORTHY Nonspecifically targeting the RAS in renovascular hypertension and ischemic nephropathy is only partially effective and also limited by class toxicities of hyperkalemia and acute decline of renal function. Our results help understand the CD PRR-mediated local mechanism in the pathogenesis of renovascular hypertension and ischemic nephropathy, and also support CD PRR as a potential therapeutic target for selective inhibition of the intrarenal RAS to treat this devastating disease.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信