Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong Pharmaceutical University, Guangzhou, China.
J Hypertens. 2021 Aug 1;39(8):1559-1566. doi: 10.1097/HJH.0000000000002809.
We have previously reported that renal medullary sphingosine-1-phosphate (S1P) regulates sodium excretion via the S1P type-1 receptor (S1PR1). As S1PR1 is predominantly expressed in collecting ducts (CD), the present study tested the hypothesis that the CD-S1PR1 pathway plays a critical role in sodium excretion and contributes to salt-sensitive hypertension.
CD-specific S1PR1 knockout mice were generated by crossing aquaporin-2-Cre mice with S1PR1-floxed mice. Renal sodium excretion and arterial pressure were compared between wild type and KO mice in response to high-salt challenges and treatment of deoxycorticosterone acetate (DOCA) salt.
Protein levels of renal medullary S1PR1 were increased by 100% after high-salt intake, whereas DOCA treatment with high-salt intake blocked the increase of S1PR1 levels. Urinary sodium excretions in knockout mice were decreased by 60% compared with wild type mice after acute intravenous sodium loading (0.84 ± 0.16 vs. 2.22 ± 0.62 μmole/min per g kwt). The pressure natriuresis was impaired in knockout mice compared with wild type mice (4.32 ± 1.04 vs. 8.73 ± 0.19 μmole/min per g kwt). The chronic high-salt intake-induced positive sodium balance was enhanced in knockout mice compared with wild type mice (5.27 ± 0.39 vs. 2.38 ± 1.04 mmol/100 g BW per 24 h). After 10-day DOCA-salt treatment, knockout mice developed more severe hypertension than wild type mice (SBP 142 ± 8 vs. 115 ± 4 mmHg).
The deletion of CD-S1PR1 reduced sodium excretion, promoted sodium retention, and accelerated DOCA-salt-induced salt-sensitive hypertension, suggesting that the CD-S1PR1 signaling is an important antihypertensive pathway by promoting sodium excretion and that impairment of renal medullary S1PR1 may represent a novel mechanism for salt-sensitive hypertension.
我们之前曾报道过，肾髓质鞘氨醇-1-磷酸（S1P）通过 S1P 型 1 受体（S1PR1）调节钠排泄。由于 S1PR1 主要在集合管（CD）中表达，本研究假设 CD-S1PR1 途径在钠排泄中起关键作用，并导致盐敏感性高血压。
通过将水通道蛋白-2-Cre 小鼠与 S1PR1 基因敲除小鼠杂交，生成 CD 特异性 S1PR1 敲除小鼠。在高盐挑战和去氧皮质酮醋酸盐（DOCA）盐处理下，比较野生型和 KO 小鼠的肾脏钠排泄和动脉压。
高盐摄入后，肾髓质 S1PR1 的蛋白水平增加了 100%，而 DOCA 治疗加高盐摄入则阻止了 S1PR1 水平的增加。与野生型小鼠相比，急性静脉内钠负荷后，敲除小鼠的尿钠排泄量减少了 60%（0.84±0.16 与 2.22±0.62μmole/min per g kwt）。与野生型小鼠相比，压力排钠受损（4.32±1.04 与 8.73±0.19μmole/min per g kwt）。与野生型小鼠相比，慢性高盐摄入引起的正钠平衡在敲除小鼠中增强（5.27±0.39 与 2.38±1.04mmol/100g BW per 24h）。在 10 天 DOCA-盐处理后，敲除小鼠比野生型小鼠发展出更严重的高血压（SBP 142±8 与 115±4mmHg）。
CD-S1PR1 的缺失减少了钠排泄，促进了钠潴留，并加速了 DOCA-盐诱导的盐敏感性高血压，这表明 CD-S1PR1 信号是通过促进钠排泄来发挥重要降压作用的途径，而肾髓质 S1PR1 的损害可能代表了盐敏感性高血压的一种新机制。
