Apocynin attenuates tubular apoptosis and tubulointerstitial fibrosis in transgenic mice independent of hypertension
Apocynin attenuates tubular apoptosis and tubulointerstitial fibrosis in transgenic mice independent of hypertension
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DOI：
10.1038/ki.2008.509
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发表时间：
2009-01-01
影响因子：
19.6
通讯作者：
Chan, John S. D.
中科院分区：
文献类型：
--
作者：
Liu, Fang;Wei, Chih-Chang;Chan, John S. D.
血管紧张素II通过增加NADPH氧化酶活性刺激活性氧的形成，这有助于促进肾损伤的促凋亡和促纤维化机制。在这里，我们确定是否夹竹桃碱，NADPH氧化酶的抑制剂，干扰肾内肾素-血管紧张素系统的作用，以尽量减少肾脏疾病的进展。在近端小管细胞中过度表达大鼠血管紧张素原的转基因小鼠被给予罗布麻、培哚普利或肼，而未经治疗或未经罗布麻治疗的非转基因幼鼠作为对照。与未经处理的非转基因小鼠相比，未经处理的转基因小鼠的收缩压、蛋白尿、活性氧产生、NADPH氧化酶活性、小管凋亡、活性caspase-3、Bax、转化生长因子- β 1、纤溶酶原激活物抑制剂-1、细胞外基质蛋白、IV型胶原和磷酸化p47phox表达显著升高。罗布宁和培哚普利能减弱这些变化；然而，夹竹桃碱对收缩压没有影响，而肼嗪可以预防高血压和小管间质纤维化，但对近端小管细胞凋亡没有影响。我们的研究表明，肾内肾素-血管紧张素系统刺激近端小管细胞凋亡和小管间质纤维化，部分是通过增强NADPH氧化酶活性和活性氧生成而独立于全体性高血压。
Angiotensin II stimulates the formation of reactive oxygen species by increased NADPH oxidase activity, which contributes to proapoptotic and profibrotic mechanisms critical in renal injury. Here we determine if apocynin, an inhibitor of NADPH oxidase, interferes with the action of the intrarenal renin-angiotensin system to minimize the progression of renal disease. Transgenic mice that overexpress rat angiotensinogen in their proximal tubule cells were given either apocynin, perindopril, or hydralazine while untreated or apocynin-treated non-transgenic littermates served as controls. Untreated transgenic mice had significant elevations of their systolic blood pressure, albuminuria, reactive oxygen species production, NADPH oxidase activity, tubular apoptosis, active caspase-3, Bax, transforming growth factor-beta 1, plasminogen activator inhibitor-1, extracellular matrix proteins, collagen type IV, and phosphorylated p47phox expression compared to untreated non-transgenic mice. Apocynin and perindopril blunted these changes; however, apocynin had no effect on the systolic blood pressure whereas hydralazine prevented hypertension and tubulointerstitial fibrosis but not proximal tubule cell apoptosis. Our study shows that the intrarenal renin-angiotensin system stimulates proximal tubule cell apoptosis and tubulointerstitial fibrosis, in part, by enhanced NADPH oxidase activity and reactive oxygen species generation independent of systemic hypertension.