Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension.

IF 5.1 Q2 CELL BIOLOGY
Function (Oxford, England) Pub Date : 2023-08-07 eCollection Date: 2023-01-01 DOI:10.1093/function/zqad043
Natalia M Mathieu, Eva M Fekete, Patricia C Muskus, Daniel T Brozoski, Ko-Ting Lu, Kelsey K Wackman, Javier Gomez, Shi Fang, John J Reho, Connie C Grobe, Ibrahim Vazirabad, Gary C Mouradian, Matthew R Hodges, Jeffrey L Segar, Justin L Grobe, Curt D Sigmund, Pablo Nakagawa
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引用次数: 0

Abstract

Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.

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脱氧皮质酮盐性高血压患者延髓腹外侧区肾素原受体基因消融对血压和水盐平衡的影响。
肾素通过与前肾素受体(PRR)相互作用的非酶激活已被认为是局部肾素-血管紧张素系统(RAS)激活的关键机制。据报道,在延髓头端腹外侧区(RVLM)存在肾素和血管紧张素原。RVLM中球螺旋体神经元的过度激活与高血压(HTN)有关。先前的研究表明,脑RAS在脱氧皮质酮(DOCA)盐HTN模型的发病机制中发挥作用。因此,我们假设RVLM中的PRR参与RAS的局部激活,促进DOCA盐HTN的发展。靶向RVLM的选择性PRR消融(PRRRVLM Null小鼠)导致DOCA盐HTN出现意外的性别依赖性和双相表型。也就是说,在DOCA盐HTN的初始阶段,PRRRVLM Null雌性(但不是雄性)在实现最大升压反应方面表现出显著延迟。雌性PRRRVLM Null随后在“维持”阶段表现出加重的DOCA盐诱导的升压反应,在DOCA盐作用13天时达到最大峰值。这种加剧的反应与对阻力小动脉和肾脏的交感神经驱动增加有关,对DOCA盐的反应加剧了液体和钠的摄入和输出,并诱导液体从细胞内到细胞外空间的动员,同时血管加压素升高。PRR的消融抑制了RVLM中参与RAS激活和儿茶酚胺合成的基因,但也诱导了参与炎症反应的基因的表达。本研究阐明了PRR在通过自主神经和神经内分泌系统对BP和水盐平衡的神经控制中的复杂和性别依赖性作用。图形摘要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.70
自引率
0.00%
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0
审稿时长
3 weeks
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