Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP
Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP
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DOI：
10.1172/jci200421382
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发表时间：
2004-09-01
影响因子：
15.9
通讯作者：
Ushikubi, F
中科院分区：
文献类型：
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作者：
Fujino, T;Nakagawa, N;Ushikubi, F
持续性肾灌注压降低通过激活肾素-血管紧张素-醛固酮系统诱导肾血管性高血压;然而，其感知机制仍不清楚。在此，我们研究了PGI（2）在体内肾血管性高血压中的作用，采用缺乏PGI（2）受体的小鼠（IP-/-小鼠）。在两肾一夹肾血管性高血压模型的WT小鼠中，BP显著升高。然而，IP-/-小鼠的BP增加显著低于WT小鼠。同样地，IP-/-小鼠对肾动脉狭窄的血浆肾素活性、肾肾素mRNA和血浆醛固酮的增加均显著低于WT小鼠。所有这些参数都是在缺乏四种PGE（2）受体亚型的小鼠中单独测量的，我们发现这些小鼠与WT小鼠具有相似的反应。PGI（2）由考克斯-2产生，该酶的选择性抑制剂SC-58125也显著降低肾动脉狭窄WT小鼠血浆肾素活性和肾素mRNA表达的增加，但IP-/-小鼠不存在这些作用。当肾素-血管紧张素-醛固酮系统被盐耗尽激活时，SC-58125减弱了WT小鼠的反应，但在IP-/-小鼠中没有。这些结果表明，来源于考克斯-2的PGI（2）在体内调节肾素释放和肾血管性高血压中起关键作用。
Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the reninangiotensin-aldosterone system; however, the sensing mechanism remains elusive. Here we investigated the role of PGI(2) in renovascular hypertension in vivo, employing mice lacking the PGI(2) receptor (IP-/- mice). In WT mice with a two-kidney, one-clip model of renovascular hypertension, the BP was significantly elevated. The increase in BP in IP-/- mice, however, was significantly lower than that in WT mice. Similarly, the increases in plasma renin activity, renal renin mRNA, and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP-/- mice than in WT mice. All these parameters were measured in mice lacking the four PGE(2) receptor subtypes individually, and we found that these mice had similar responses to WT mice. PGI(2) is produced by COX-2 and a selective inhibitor of this enzyme, SC-58125, also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis, but these effects were absent in IP-/- mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, SC-58125 blunted the response in WT mice but not in IP-/- mice. These results indicate that PGI(2) derived from COX-2 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo.