肾脏和交感神经的综合机制是性别和年龄依赖性高血压以及血压盐敏感性发展的基础。

IF 5.3 2区 医学 Q1 GERIATRICS & GERONTOLOGY
GeroScience Pub Date : 2024-12-01 Epub Date: 2024-07-08 DOI:10.1007/s11357-024-01266-1
Alissa A Frame, Kayla M Nist, Kiyoung Kim, Franco Puleo, Jesse D Moreira, Hailey Swaldi, James McKenna, Richard D Wainford
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引用次数: 0

摘要

衰老是一种不可改变的高血压风险因素,但对其研究不足。我们假设,交感神经介导的肾脏钠重吸收激活驱动了年龄依赖性高血压和血压(BP)的盐敏感性。我们以 3 个月、8 个月和 16 个月大的雌雄 Sprague-Dawley 大鼠为正常衰老模型,评估了血压、交感神经张力指数以及对急性和慢性钠挑战的生理反应,包括氯化钠共转运体(NCC)调节。我们还评估了肾神经消融和 NCC 拮抗对高血压雄性大鼠的影响。我们观察到性别依赖性肾脏钠处理受损(24 小时钠平衡(meq),雄性 3 个月 0.36 ± 0.1 vs. 16 个月 0.84 ± 0.2;5% 体重等渗盐水容量扩张期间排泄的钠负荷(%),雄性 3 个月 77 ± 5 vs. 16 个月 22 ± 8)、高血压(MAP(mmHg),雄性 3 个月 123 ± 4 vs. 16 个月 148 ± 6)以及老龄雄性大鼠(而非雌性)血压的盐敏感性。交感抑制传入肾神经(ARN)反应减弱导致雄性大鼠交感神经张力增强和高血压。交感神经张力增强会导致肾钠潴留,部分原因是通过与赖氨酸激酶(WNK)STE20/SPS1相关的脯氨酸/富含丙氨酸的激酶信号通路功能失调增加了NCC活性,从而驱动了高血压和老年雄性大鼠血压的盐敏感性。NCC拮抗剂和肾神经消融减少了WNK功能障碍并降低了NCC活性,从而减轻了雄性Sprague-Dawley大鼠的年龄依赖性高血压。交感抑制性 ARN 反射受损,通过 WNK1/WNK4 动态受损,以 NCC 依赖性方式导致性别和年龄依赖性高血压,这表明该途径是治疗年龄依赖性高血压的一个基于机制的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Integrated renal and sympathetic mechanisms underlying the development of sex- and age-dependent hypertension and the salt sensitivity of blood pressure.

Integrated renal and sympathetic mechanisms underlying the development of sex- and age-dependent hypertension and the salt sensitivity of blood pressure.

Aging is a non-modifiable understudied risk factor for hypertension. We hypothesized that sympathetically mediated activation of renal sodium reabsorption drives age-dependent hypertension and the salt sensitivity of blood pressure (BP). Using 3-, 8-, and 16-month-old male and female Sprague-Dawley rats as a model of normal aging, we assessed BP, indices of sympathetic tone, and the physiological responses to acute and chronic sodium challenge including sodium chloride cotransporter (NCC) regulation. The effects of renal nerve ablation and NCC antagonism were assessed in hypertensive male rats. We observed sex-dependent impaired renal sodium handling (24 h sodium balance (meq), male 3-month 0.36 ± 0.1 vs. 16-month 0.84 ± 0.2; sodium load excreted during 5% bodyweight isotonic saline volume expansion (%) male 3-month 77 ± 5 vs. 16-month 22 ± 8), hypertension (MAP (mmHg) male 3-month 123 ± 4 vs. 16-month 148 ± 6), and the salt sensitivity of BP in aged male, but not female, rats. Attenuated sympathoinhibitory afferent renal nerve (ARN) responses contributed to increased sympathetic tone and hypertension in male rats. Increased sympathetic tone contributes to renal sodium retention, in part through increased NCC activity via a dysfunctional with-no-lysine kinase-(WNK) STE20/SPS1-related proline/alanine-rich kinase signaling pathway, to drive hypertension and the salt sensitivity of BP in aged male rats. NCC antagonism and renal nerve ablation, which reduced WNK dysfunction and decreased NCC activity, attenuated age-dependent hypertension in male Sprague-Dawley rats. The contribution of an impaired sympathoinhibitory ARN reflex to sex- and age-dependent hypertension in an NCC-dependent manner, via an impaired WNK1/WNK4 dynamic, suggests this pathway as a mechanism-based target for the treatment of age-dependent hypertension.

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来源期刊
GeroScience
GeroScience Medicine-Complementary and Alternative Medicine
CiteScore
10.50
自引率
5.40%
发文量
182
期刊介绍: GeroScience is a bi-monthly, international, peer-reviewed journal that publishes articles related to research in the biology of aging and research on biomedical applications that impact aging. The scope of articles to be considered include evolutionary biology, biophysics, genetics, genomics, proteomics, molecular biology, cell biology, biochemistry, endocrinology, immunology, physiology, pharmacology, neuroscience, and psychology.
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