Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1
Prostaglandins that increase renin production in response to ACE inhibition are not derived from cyclooxygenase-1
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DOI：
10.1152/ajpregu.00150.2002
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发表时间：
2002-09-01
影响因子：
2.8
通讯作者：
Harris, RC
中科院分区：
文献类型：
--
作者：
Cheng, HF;Wang, SW;Harris, RC
众所周知，非选择性、非甾体类抗炎药可抑制肾素的产生。我们之前的研究表明，在环氧化酶(COX)-2选择性抑制剂治疗的大鼠和COX-2 -/-小鼠中，血管紧张素转换酶抑制剂（ACEI）介导的肾素增加不存在。目前的研究进一步研究了COX-1是否也参与介导acei诱导的肾素产生。由于肾素的增加是由cAMP介导的，我们还研究了肾素的增加是否由前列腺素E-2受体EP2亚型介导，该亚型与G(s)偶联并增加cAMP。因此，我们研究了COX-1或EP2的基因缺失是否会阻止acei诱导的肾素表达增加。给予年龄和性别匹配的野生型（+/+）和纯合子型（-/-）小鼠卡托普利7 d，测定血浆和肾肾素水平及肾肾素mRNA表达。COX-1 +/+和cox -/-小鼠血浆或肾组织肾素活性基础水平无显著差异。卡托普利同样增加肾素[血浆肾素活性（PRA）： +/+ 9.3 +/- 2.2 vs. 50.1 +/- 10.9；- / - 13.7 + / - 1.5和43.9 + / - 6.6 ng ANG I.ml (1) . h (1);肾素浓度：+/+ 11.8 +/- 1.7 vs. 35.3 +/- 3.9；- / - 13.0 + / - 3.0和27.8 + / - 2.7 ng ANG I.mg蛋白质(1). h (1);N = 6；加与不加卡托普利组P < 0.05。ACEI还增加了肾素mRNA的表达（+/+ 2.4 +/- 0.2;-/- 2.1 +/- 0.2倍对照；n = 6-10; P < 0.05）。与+/+相比，卡托普利导致EP2 -/-类似的增加。COX-2抑制剂SC-58236阻断acei诱导的EP2缺失小鼠肾素浓度升高(+/+ 24.7 +/- 1.7 vs. 9.8 +/- 0.4; -/- 21.1 +/- 3.2 vs. 9.3 +/- 0.4 ng ANG .mg蛋白（-1）\h(-1)；n = 5)以及COX-1 - / -小鼠(sc - 58236治疗PRA: + / + 7.3 + / - 0.6; - / - 8.0 + / - 0.9 ng ANG I.ml (1) . h (1);肾素：+/+ 9.1 +/- 0.9；-/- 9.6 +/- 0.5 ng ANG .mg protein(-1).h(-1)；N = 6-7；P < 0.05)。肾素表达的免疫组化分析证实了上述结果。这项研究提供了明确的证据，证明代谢产物COX-2而不是COX-1介导acei诱导的肾素增加。EP2的持续应答提示前列腺素E-2受体亚型4和/或前列腺环素受体（IP）的参与。
It is well known that nonselective, nonsteroidal anti-inflammatory drugs inhibit renal renin production. Our previous studies indicated that angiotensin-converting enzyme inhibitor (ACEI)-mediated renin increases were absent in rats treated with a cyclooxygenase (COX)-2-selective inhibitor and in COX-2 -/- mice. The current study examined further whether COX-1 is also involved in mediating ACEI-induced renin production. Because renin increases are mediated by cAMP, we also examined whether increased renin is mediated by the prostaglandin E-2 receptor EP2 subtype, which is coupled to G(s) and increases cAMP. Therefore, we investigated if genetic deletion of COX-1 or EP2 prevents increased ACEI-induced renin expression. Age- and gender-matched wild-type (+/+) and homozygous null mice (-/-) were administered captopril for 7 days, and plasma and renal renin levels and renal renin mRNA expression were measured. There were no significant differences in the basal level of renal renin activity from plasma or renal tissue in COX-1 +/+ and -/- mice. Captopril administration increased renin equally [plasma renin activity (PRA): +/+ 9.3 +/- 2.2 vs. 50.1 +/- 10.9; -/- 13.7 +/- 1.5 vs. 43.9 +/- 6.6 ng ANG I.ml(-1).h(-1); renal renin concentration: +/+ 11.8 +/- 1.7 vs. 35.3 +/- 3.9; -/- 13.0 +/- 3.0 vs. 27.8 +/- 2.7 ng ANG I.mg protein(-1).h(-1); n = 6; P < 0.05 with or without captopril]. ACEI also increased renin mRNA expression (+/+ 2.4 +/- 0.2; -/- 2.1 +/- 0.2 fold control; n = 6-10; P < 0.05). Captopril led to similar increases in EP2 -/- compared with +/+. The COX-2 inhibitor SC-58236 blocked ACEI-induced elevation in renal renin concentration in EP2 null mice (+/+ 24.7 +/- 1.7 vs. 9.8 +/- 0.4; -/- 21.1 +/- 3.2 vs. 9.3 +/- 0.4 ng ANG I.mg protein(-1).\h(-1); n = 5) as well as in COX-1 -/- mice (SC-58236-treated PRA: +/+ 7.3 +/- 0.6; -/- 8.0 +/- 0.9 ng ANG I.ml(-1).h(-1); renal renin: +/+ 9.1 +/- 0.9; -/- 9.6 +/- 0.5 ng ANG I.mg protein(-1).h(-1); n = 6-7; P < 0.05 compared with no treatment). Immunohistochemical analysis of renin expression confirmed the above results. This study provides definitive evidence that metabolites of COX-2 rather than COX-1 mediate ACEI-induced renin increases. The persistent response in EP2 nulls suggests involvement of prostaglandin E-2 receptor subtype 4 and/or prostacyclin receptor (IP).