Intracellular cholesterol stimulates ENaC by interacting with phosphatidylinositol-4,5-bisphosphate and mediates cyclosporine A-induced hypertension
Intracellular cholesterol stimulates ENaC by interacting with phosphatidylinositol-4,5-bisphosphate and mediates cyclosporine A-induced hypertension
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细胞内胆固醇通过与 4,5-二磷酸磷脂酰肌醇相互作用刺激 ENaC，并介导环孢素 A 诱导的高血压
DOI：
10.1016/j.bbadis.2018.08.027
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发表时间：
2019-07-01
影响因子：
6.2
通讯作者：
Ma, He-Ping
中科院分区：
文献类型：
--
作者：
Zhai, Yu-Jia;Wu, Ming-Ming;Ma, He-Ping
我们先前已经证明，用环孢素A(CsA)阻断ATP结合盒转运体A1(ABCA1)可以刺激培养的远端肾单位细胞上皮钠通道(ENaC)。在这里，我们显示CsA使野生型和载脂蛋白E(ApoE)基因敲除(KO)小鼠的收缩压升高到相似的水平。洛伐他汀抑制胆固醇(CHO)合成可完全逆转收缩压升高。膜片钳数据显示细胞内CHO通过与ENaC激活剂磷脂酰肌醇-4，5-二磷酸(PIP2)相互作用来刺激培养的远端肾单位细胞的ENaC。共聚焦显微镜数据显示，α-ENaC和PIP2均以CHO依赖机制定位于微绒毛。膜CHO的缺失降低了顶膜中γ-ENaC的水平。与年轻小鼠相比，老年小鼠ABCA1表达降低，细胞内CHO升高。同时，来自分裂开放的皮质集合管的细胞附着式膜片钳数据显示，老年小鼠的ENaC活性显著增加。这些数据表明，阻断ABCA1导致的细胞内CHO升高刺激ENaC，这可能是CsA诱导的高血压的原因之一。这项研究还表明，ABCA1表达降低可能通过细胞内CHO升高而增加ENaC活性，从而介导年龄相关性高血压。
We have previously shown that blockade of ATP-binding cassette transporter A1 (ABCA1) with cyclosporine A (CsA) stimulates the epithelial sodium channel (ENaC) in cultured distal nephron cells. Here we show that CsA elevated systolic blood pressure in both wild-type and apolipoprotein E (ApoE) knockout (KO) mice to a similar level. The elevated systolic blood pressure was completely reversed by inhibition of cholesterol (Cho) synthesis with lovastatin. Inside-out patch-clamp data show that intracellular Cho stimulated ENaC in cultured distal nephron cells by interacting with phosphatidylinositol-4,5-bisphosphate (PIP2), an ENaC activator. Confocal microscopy data show that both alpha-ENaC and PIP2 were localized in microvilli via a Cho-dependent mechanism. Deletion of membrane Cho reduced the levels of gamma-ENaC in the apical membrane. Reduced ABCA1 expression and elevated intracellular Cho were observed in old mice, compared to young mice. In parallel, cell-attached patch-clamp data from the split-open cortical collecting ducts (CCD) show that ENaC activity was significantly increased in old mice. These data suggest that elevation of intracellular Cho due to blockade of ABCA1 stimulates ENaC, which may contribute to CsA-induced hypertension. This study also implies that reduced ABCA1 expression may mediate age-related hypertension by increasing ENaC activity via elevation of intracellular Cho.