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.

衰老是高血压的一个不可改变的未被充分研究的危险因素。我们假设交感神经介导的肾钠重吸收激活会导致年龄依赖性高血压和血压 （BP） 的盐敏感性。使用 3 、 8 和 16 个月大的雄性和雌性 Sprague-Dawley 大鼠作为正常衰老的模型，我们评估了血压、交感神经张力指数以及对急性和慢性钠挑战的生理反应，包括氯化钠协同转运蛋白 （NCC） 调节。评估肾神经消融术和 NCC 拮抗作用对高血压雄性大鼠的影响。我们观察到性别依赖性肾钠处理受损（24 小时钠平衡 （meq），男性 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钠负荷排泄 （%） 男性 3 个月 77 ± 5 vs. 16 个月 22 ± 8），高血压 （MAP （mmHg） 男性 3 个月 123 ± 4 vs. 16 个月 148 ± 6），以及老年男性血压的盐敏感性， 但不是雌性大鼠。交感神经抑制性传入肾神经 （ARN） 反应减弱导致雄性大鼠交感神经张力增加和高血压。交感神经张力增加导致肾钠潴留，部分原因是通过功能失调的无赖氨酸激酶 （WNK） STE20/SPS1 相关的富含脯氨酸/丙氨酸的激酶信号通路增加 NCC 活性，从而驱动高血压和老年雄性大鼠的血压盐敏感性。NCC 拮抗作用和肾神经消融术减少了 WNK 功能障碍并降低了 NCC 活性，减轻了雄性 Sprague-Dawley 大鼠的年龄依赖性高血压。 交感神经抑制性 ARN 反射受损通过 WNK1/WNK4 动力学受损以 NCC 依赖性方式对性别和年龄依赖性高血压的贡献，表明该通路是治疗年龄依赖性高血压的基于机制的靶点。