NOX2 is the primary source of angiotensin II-induced superoxide in the macula densa
NOX2 is the primary source of angiotensin II-induced superoxide in the macula densa
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DOI：
10.1152/ajpregu.00762.2009
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发表时间：
2010-03-01
影响因子：
2.8
通讯作者：
Liu, Ruisheng
中科院分区：
文献类型：
--
作者：
Fu, Yiling;Zhang, Rui;Liu, Ruisheng
傅勇，张荣，陆东，刘华，钱德拉谢卡·K，Juncos LA，Liu R.NOX2是血管紧张素II诱导的致密黄斑超氧化物的主要来源。Am J Physiol Regul Integr Comp Physiol 298：R707-R712,2010.2010年1月6日首次出版；DOI：10.1152/ajpregu.00762.2009。-致密黄斑(MD)通过肾小管球反馈介导的肾脏血流动力学调节受超氧化物(O-2(-))和血管紧张素II(Ang II)等因素之间的相互作用调节。我们已经报道，盐诱导的MD中的O-2(-)是由NADPH氧化酶(NOX)的NOX2亚型产生的；然而，Ang II诱导MD中的O-2(-)的来源尚不清楚。因此，我们通过测量Ang II处理的MMDD1细胞(一种MD样细胞系)中的O-2(-)，确定了Ang II增加MD中O-2(-)的途径。Ang II使MMDD1O-2(-)水平增加一倍以上(P<；0.01)。这种增加可被AT(1)受体阻断剂氯沙坦阻断，但不能被AT(2)受体拮抗剂PD-123319阻断。NOX抑制剂apocynin可使O-2(-)减少86%(P<；0.01)，而黄嘌呤醇和环氧合酶-2抑制剂NS-398则无明显作用。NOX依赖的O-2(-)增加是由于NOX2亚型；针对NOX2的短干扰(Si)RNA可钝化Ang II诱导的O-2(-)增加，而NOX4/siRNA不能。最后，我们发现抑制NOX的rac1亚基可以钝化Ang II诱导的NOX4/siRNA处理细胞中O-2(-)的产生，但不会进一步减少NOX2/siRNA处理细胞中的O-2(-)生成。我们的结果表明，Ang II主要通过AT(1)依赖的NOX2激活刺激MD产生O-2(-)。完全激活NOX2需要rac1。这一通路可能是血管紧张素转换酶II增强肾小管球反馈的重要组成部分。
Fu Y, Zhang R, Lu D, Liu H, Chandrashekar K, Juncos LA, Liu R. NOX2 is the primary source of angiotensin II-induced superoxide in the macula densa. Am J Physiol Regul Integr Comp Physiol 298: R707-R712, 2010. First published January 6, 2010; doi:10.1152/ajpregu.00762.2009.-Macula densa (MD)-mediated regulation of renal hemodynamics via tubuloglomerular feedback is regulated by interactions between factors such as superoxide (O-2(-)) and angiotensin II (ANG II). We have reported that NaCl-induced O-2(-) in the MD is produced by the NOX2 isoform of NADPH oxidase (NOX); however, the source of ANG II-induced O-2(-) in MD is unknown. Thus we determined the pathways by which ANG II increased O-2(-) in the MD by measuring O-2(-) in ANG II-treated MMDD1 cells, a MD-like cell line. ANG II caused MMDD1 O-2(-) levels to increase by more than twofold (P < 0.01). This increase was blocked by losartan (AT(1) receptor blocker) but not PD-123319 (AT(2) receptor antagonist). Apocynin (a NOX inhibitor) decreased O-2(-) by 86% (P < 0.01), whereas oxypurinol (a xanthine oxidase inhibitor) and NS-398 (a cyclooxygenase-2 inhibitor) had no significant effect. The NOX-dependent increase in O-2(-) was due to the NOX2 isoform; a short interfering (si) RNA against NOX2 blunted ANG II-induced increases in O-2(-), whereas the NOX4/siRNA did not. Finally, we found that inhibiting the Rac1 subunit of NOX blunted ANG II-induced O-2(-) production in NOX4/siRNA-treated cells but did not further decrease it in NOX2/siRNA-treated cells. Our results indicate that ANG II stimulates O-2(-) production in the MD primarily via AT(1)-dependent activation of NOX2. Rac1 is required for the full activation of NOX2. This pathway may be an important component of ANG II enhancement of tubuloglomerular feedback.