Collecting duct-specific knockout of sphingosine-1-phosphate receptor 1 aggravates DOCA-salt hypertension in mice.
Collecting duct-specific knockout of sphingosine-1-phosphate receptor 1 aggravates DOCA-salt hypertension in mice.
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DOI：
10.1097/hjh.0000000000002809
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发表时间：
2021-08-01
影响因子：
4.9
通讯作者：
Li N
中科院分区：
文献类型：
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作者：
Hu G;Zhu Q;Wang W;Xie D;Chen C;Li PL;Ritter JK;Li N
我们之前报道过肾髓鞘鞘醇-1-磷酸（S1P）通过S1P 1型受体（S1PR1）调节钠排泄。由于S1PR1主要在集管（CD）中表达，本研究验证了CD-S1PR1通路在钠排泄中起关键作用并导致盐敏感性高血压的假设。通过水通道蛋白-2- cre小鼠与S1PR1粘接小鼠杂交，产生cd特异性S1PR1敲除（KO）小鼠。比较野生型（WT）和KO小鼠对高盐刺激和醋酸脱氧皮质酮（DOCA）盐处理的肾钠排泄和动脉压。高盐摄入（HS）后，肾髓质S1PR1蛋白水平升高100%，而DOCA + HS可阻断S1PR1蛋白水平的升高。急性静脉钠负荷后，KO小鼠尿钠排泄量比WT小鼠减少50%（3.35±0.28 μmol/min/g kwt比6.87±1.44 μmol/min/g kwt）。与WT小鼠相比，KO小鼠的压力尿钠功能明显受损（4.22±0.61比10.76±1.30 μmol /min/g kwt）。与WT小鼠相比，KO小鼠慢性hs诱导的钠正平衡增强（6.48±0.28比2.38±0.06 mmol /100g BW/24h）。经过10天的doca盐治疗，KO小鼠比WT小鼠出现更严重的高血压（收缩压142±8比115±4 mmHg）。CD-S1PR1的缺失减少了钠排泄，促进了钠潴留，加速了doca盐诱导的盐敏感性高血压，提示CD-S1PR1信号通路通过促进钠排泄是一个重要的降压途径，肾髓质S1PR1损伤可能是盐敏感性高血压的新机制。
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 (KO) mice were generated by crossing aquaporin-2-Cre mice with S1PR1-floxed mice. Renal sodium excretion and arterial pressure were compared between wild-type (WT) 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 (HS), whereas DOCA treatment + HS blocked the increase of S1PR1 levels. Urinary sodium excretions in KO mice were decreased by 50% compared with WT mice after acute IV sodium loading (3.35±0.28 vs. 6.87±1.44 μmol/min/g kwt). The pressure natriuresis was impaired in KO mice compared with WT mice (4.22±0.61 vs. 10.76±1.30 μmole/min/g kwt). The chronic HS-induced positive sodium balance was enhanced in KO mice compared with WT mice (6.48±0.28 vs. 2.38±0.06 mmole/100g BW/24h). After 10-day DOCA-salt treatment, KO mice developed more severe hypertension than WT mice (systolic blood pressure 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 anti-hypertensive pathway by promoting sodium excretion and that impairment of renal medullary S1PR1 may represent a novel mechanism for salt-sensitive hypertension.