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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.
摘要：
肾素通过与肾素原受体（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。肾素和血管紧张素原在延髓头端腹外侧（RVLM）的存在。RVLM中球脊髓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模型的发病机理中起作用。因此，我们假设RVLM中的PRR参与了RAS的局部激活，促进DOCA-盐HTN的发展。靶向RVLM(PRRRVLM-Null小鼠)的选择性PRR消融在DOCA-盐HTN中导致意外的性别依赖性和双相表型。也就是说,PRRRVLM-Null雌性（而非雄性）在DOCA-盐HTN的初始阶段实现最大升压反应方面表现出明显的延迟。雌性PRRRVLM-Null随后在“维持”阶段显示出DOCA盐引起的升压反应加剧，在DOCA盐的第13天达到最大峰值。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，由于DOCA盐，液体和钠的摄入和输出加剧，并诱导液体从细胞内到细胞外空间的动员，伴随着血管加压素的升高。PRR的消融抑制了RVLM中与RAS激活和儿茶酚胺合成有关的基因，但也诱导了与炎症反应有关的基因的表达。这项研究说明了PRR通过自主神经和神经内分泌系统在BP和水矿物质平衡的神经控制中的复杂和性别依赖性作用。图形抽象。
