Renal tubule angiotensin II type 1 receptor-associated protein promotes natriuresis and inhibits salt-sensitive blood pressure elevation.
Renal tubule angiotensin II type 1 receptor-associated protein promotes natriuresis and inhibits salt-sensitive blood pressure elevation.
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DOI：
10.1161/jaha.114.001594
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发表时间：
2015-03-19
影响因子：
5.4
通讯作者：
Umemura S
中科院分区：
文献类型：
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作者：
Wakui H;Uneda K;Tamura K;Ohsawa M;Azushima K;Kobayashi R;Ohki K;Dejima T;Kanaoka T;Tsurumi-Ikeya Y;Matsuda M;Haruhara K;Nishiyama A;Yabana M;Fujikawa T;Yamashita A;Umemura S
血管紧张素II 1型受体相关蛋白(ATRAP；AgTrap基因)促进AT1R内化，同时抑制病理性AT1R的激活。在这项研究中，我们使用盐敏感的C57BL/6J背景下的ATRAP转基因小鼠，研究了肾远端小管ATRAP的增强是否影响了高盐负荷下的钠处理和血压调节。肾ATRAP转基因小鼠(rATRAP-TG)表现为肾小管显性ATRAP增强，其野生型产仔C57BL/6J小鼠在基础水平的正常盐饮食(0.3%氯化钠)下接受7天的HS负荷(4%氯化钠)。在rATRAP-TG小鼠中，与野生型小鼠相比，饮食HS负荷介导的血压升高受到抑制，尽管基线血压相似。尽管rATRAP-TG小鼠和野生型小鼠在HS负荷前后肾脏血管紧张素II水平相似，但HS负荷后rATRAP-TG小鼠的尿钠排泄显著增加。此外，与野生型小鼠相比，rATRAP-TG小鼠在生理盐水扩容条件下对阿米洛利敏感的上皮Na+通道的功能转运活性显著降低，而上皮Na+通道蛋白的表达没有明显变化。与野生型小鼠相比，rATRAP-TG小鼠肾脏质膜AT1R表达降低。这些结果表明，ATRAP的远端小管优势增强抑制了病理性的肾脏钠重吸收和对HS负荷所致的血压升高。这些发现表明，ATRAP介导的肾远端小管钠处理的调节可能是盐敏感性血压调节的一个感兴趣的靶点。
Angiotensin II type 1 receptor (AT1R)–associated protein (ATRAP; Agtrap gene) promotes AT1R internalization along with suppression of pathological AT1R activation. In this study, we examined whether enhancement of ATRAP in the renal distal tubules affects sodium handling and blood pressure regulation in response to high salt (HS) loading, using ATRAP transgenic mice on a salt‐sensitive C57BL/6J background. Renal ATRAP transgenic (rATRAP‐Tg) mice, which exhibit renal tubule–dominant ATRAP enhancement, and their wild‐type littermate C57BL/6J mice on a normal salt diet (0.3% NaCl) at baseline were subjected to dietary HS loading (4% NaCl) for 7 days. In rATRAP‐Tg mice, the dietary HS loading–mediated blood pressure elevation was suppressed compared with wild‐type mice, despite similar baseline blood pressure. Although renal angiotensin II level was comparable in rATRAP‐Tg and wild‐type mice with and without HS loading, urinary sodium excretion in response to HS loading was significantly enhanced in the rATRAP‐Tg mice. In addition, functional transport activity of the amiloride‐sensitive epithelial Na+ channel was significantly decreased under saline volume–expanded conditions in rATRAP‐Tg mice compared with wild‐type mice, without any evident change in epithelial Na+ channel protein expression. Plasma membrane AT1R expression in the kidney of rATRAP‐Tg mice was decreased compared with wild‐type mice. These results demonstrated that distal tubule–dominant enhancement of ATRAP inhibits pathological renal sodium reabsorption and blood pressure elevation in response to HS loading. The findings suggest that ATRAP‐mediated modulation of sodium handling in renal distal tubules could be a target of interest in salt‐sensitive blood pressure regulation.