Aldosterone-induced kidney injury is mediated by NFκB activation.
Aldosterone-induced kidney injury is mediated by NFκB activation.
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DOI：
10.1007/s10157-010-0373-1
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发表时间：
2011-03
影响因子：
2.3
通讯作者：
Hayashi M
中科院分区：
文献类型：
--
作者：
Fukuda S;Horimai C;Harada K;Wakamatsu T;Fukasawa H;Muto S;Itai A;Hayashi M
醛固酮可诱导肾脏炎症和纤维化，而核因子κB（NFκB）在多种细胞因子介导的炎症中起关键作用。在此，我们确定NFκB活化在醛固酮诱导的肾损伤中的作用。我们使用单侧肾切除大鼠，持续或不持续醛固酮输注和0.9%生理盐水作为饮用水3周。经口给予IKKβ抑制剂IMD-1041和螺内酯，分别抑制NFκB和盐皮质激素受体。注入醛固酮的大鼠表现出严重的肾损伤、高血压和促炎和纤维化蛋白、骨桥蛋白、纤维蛋白原、I型胶原和派-1的表达增加。蛋白质印迹法证实了NFκB通过增加肾脏核部分中p65的量而被醛固酮激活，口服IMD-1041防止了肾损伤并减少了促炎蛋白和纤维化蛋白的增加，而血压没有显著变化。此外，血管紧张素转换酶2（ACE 2），这已被发现作为一种保护因素，在各种肾损伤模型的变化，进行了检查。免疫荧光研究显示，ACE 2的存在下，刷状缘膜的近曲小管和显着钝化ACE 2染色的醛固酮注入大鼠。通过蛋白质印迹法证实了ACE 2蛋白量的减少，并且IMD-1041也防止了ACE 2的减少。螺内酯的管理也取消了醛固酮的影响。我们的研究结果表明，醛固酮通过激活NFκB和盐皮质激素受体诱导肾损伤，ACE 2表达减少可能在醛固酮诱导的肾损伤中起重要作用。
Aldosterone induces inflammation and fibrosis in the kidney, while nuclear factor κB (NFκB) plays key roles in inflammation mediated by various cytokines. Here, we determined the roles of NFκB activation in aldosterone-induced kidney injury. We used unilaterally nephrectomized rats with or without continuous aldosterone infusion and 0.9% saline as drinking water for 3 weeks. IMD-1041, an IKKβ inhibitor, and spironolactone were orally administered to inhibit NFκB and mineralocorticoid receptor, respectively. The aldosterone-infused rats exhibited severe kidney injury, hypertension, and increased expression of pro-inflammatory and fibrotic proteins, osteopontin, fibrinogen, collagen type I, and PAI-1. Western blotting confirmed NFκB activation by aldosterone by the increased amount of p65 in the nuclear fraction of the kidney, and oral IMD-1041 prevented the kidney injury and lessened the increase in pro-inflammatory and fibrotic proteins without significant changes in blood pressures. In addition, changes in angiotensin-converting enzyme 2 (ACE2), which has been found to act as a protective factor in various kidney injury models, were examined. Immunofluorescence studies revealed the presence of ACE2 in the brush-border membrane of the proximal convoluted tubules and markedly blunted ACE2 staining in aldosterone-infused rats. The decrease in amount of ACE2 protein was confirmed by Western blotting, and IMD-1041 also prevented the decrease in ACE2. The administration of spironolactone also abolished the effects of aldosterone. Our results suggest that aldosterone induces kidney injury via activation of NFκB and mineralocorticoid receptor, and that decreased ACE2 expression may play an important role in aldosterone-induced kidney injury.
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影响因子：
19.6
作者：
Tikellis, C.;Cooper, M. E.;Thomas, M. C.
通讯作者：
Thomas, M. C.
影响因子：
64.5
作者：
Smale, Stephen T.
通讯作者：
Smale, Stephen T.
DOI：
10.1152/ajpheart.00549.2006
发表时间：
2007-01-01
影响因子：
4.8
作者：
Onai, Yasuyuki;Suzuki, Jun-ichi;Isobe, Mitsuaki
通讯作者：
Isobe, Mitsuaki
影响因子：
8.3
作者：
Bergmann, Astrid;Eulenberg, Claudia;Kettritz, Ralph
通讯作者：
Kettritz, Ralph
影响因子：
10.8
作者：
Onai, Y;Suzuki, J;Isobe, M
通讯作者：
Isobe, M