Cell-Specific Actions of the Prostaglandin E-Prostanoid Receptor 4 Attenuating Hypertension: A Dominant Role for Kidney Epithelial Cells Compared With Macrophages.
Cell-Specific Actions of the Prostaglandin E-Prostanoid Receptor 4 Attenuating Hypertension: A Dominant Role for Kidney Epithelial Cells Compared With Macrophages.
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DOI：
10.1161/jaha.122.026581
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发表时间：
2022-10-04
影响因子：
5.4
通讯作者：
Coffman, Thomas M.
中科院分区：
文献类型：
--
作者：
Yang, Ting;Song, Chengcheng;Ralph, Donna L.;Andrews, Portia;Sparks, Matthew A.;Koller, Beverly H.;McDonough, Alicia A.;Coffman, Thomas M.
临床研究表明，非甾体抗炎药会阻断所有前列腺素的产生，导致钠潴留并加重高血压，这提示前列腺素在高血压中具有有益作用。在前列腺素中，前列腺素E2及其E -前列腺素受体4（EP4R）与血压控制有关。我们之前的研究发现，在成年小鼠的所有组织中有条件地缺失EP4R会加重血管紧张素II依赖性高血压，这表明EP4R具有强大的抵抗血压升高的作用。我们还发现，从血管平滑肌细胞中去除EP4R并不影响高血压的严重程度，这表明前列腺素E的非血管靶点介导了这种抗高血压作用。
在此，我们制备了巨噬细胞特异性EP4受体敲除小鼠或肾上皮细胞（KEKO）特异性缺失EP4R的小鼠，以评估这些细胞中的EP4R对高血压发病机制的作用。巨噬细胞特异性EP4受体敲除小鼠在饮食钠变化或慢性血管紧张素II输注时的血压反应与对照组相似。相比之下，与对照组（平均动脉压：137±4 mmHg）相比，KEKO小鼠的血管紧张素II依赖性高血压显著加重（平均动脉压：146±3 mmHg；P = 0.02），同时KEKO小鼠伴有钠排泄受损。由于肾脏中EP4R的表达在集合管中富集，我们比较了血管紧张素II输注的KEKO小鼠和对照组对阿米洛利的反应。与对照组相比，用阿米洛利阻断上皮钠通道导致KEKO小鼠的钠排泄过度（每20g体重每24小时0.21±0.01 mmol对0.15±0.02 mmol；P = 0.015）。
我们的数据表明肾上皮中的EP4R可减轻高血压。EP4R的这种抗高血压作用可能是通过降低上皮钠通道的活性，从而促进钠排泄来介导的。
A beneficial role for prostanoids in hypertension is suggested by clinical studies showing nonsteroidal anti‐inflammatory drugs, which block the production of all prostanoids, cause sodium retention and exacerbate hypertension. Among prostanoids, prostaglandin E2 and its E‐prostanoid receptor 4 receptor (EP4R) have been implicated in blood pressure control. Our previous study found that conditional deletion of EP4R from all tissues in adult mice exacerbates angiotensin II‐dependent hypertension, suggesting a powerful effect of EP4R to resist blood pressure elevation. We also found that elimination of EP4R from vascular smooth muscle cells did not affect the severity of hypertension, suggesting nonvascular targets of prostaglandin E mediate this antihypertensive effect. Here we generated mice with cell‐specific deletion of EP4R from macrophage‐specific EP4 receptor knockouts or kidney epithelial cells (KEKO) to assess the contributions of EP4R in these cells to hypertension pathogenesis. Macrophage‐specific EP4 receptor knockouts showed similar blood pressure responses to alterations in dietary sodium or chronic angiotensin II infusion as Controls. By contrast, angiotensin II‐dependent hypertension was significantly augmented in KEKOs (mean arterial pressure: 146±3 mm Hg) compared with Controls (137±4 mm Hg; P=0.02), which was accompanied by impaired natriuresis in KEKOs. Because EP4R expression in the kidney is enriched in the collecting duct, we compared responses to amiloride in angiotensin II‐infused KEKOs and Controls. Blockade of the epithelial sodium channel with amiloride caused exaggerated natriuresis in KEKOs compared with Controls (0.21±0.01 versus 0.15±0.02 mmol/24 hour per 20 g; P=0.015). Our data suggest EP4R in kidney epithelia attenuates hypertension. This antihypertension effect of EP4R may be mediated by reducing the activity of the epithelial sodium channel, thereby promoting natriuresis.