Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity
Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity
复制标题
DOI：
10.1152/ajprenal.00655.2013
复制
发表时间：
2014-04-01
影响因子：
4.2
通讯作者：
Oudit, Gavin Y.
中科院分区：
文献类型：
--
作者：
Mori, Jun;Patel, Vaibhav B.;Oudit, Gavin Y.
肾素-血管紧张素系统，尤其是血管紧张素Ⅱ(Ang II)在糖尿病肾病的发生发展中起着关键作用。Ang 1-7对Ang II有拮抗作用，已知对糖尿病肾病有有益作用。我们研究了血管紧张素转换酶1-7对db/db小鼠糖尿病肾病的有益作用机制。我们通过植入的微渗泵给5个月龄的db/db小鼠注射血管紧张素1-7(0.5mg.kg(-1).day(-1))或生理盐水28天。Ang 1-7治疗减轻了db/db小鼠的肾脏重量，改善了系膜扩张，增加了尿白蛋白排泄，这是糖尿病肾病的特征。Ang1-7可减轻db/db小鼠肾脏纤维化，这与信号转导和转录激活子3(STAT3)途径的去磷酸化有关。Ang 1-7治疗还通过减弱NADPH氧化酶活性和减轻肾周脂肪组织的炎症来抑制活性氧的产生。此外，Ang1-7治疗减少了db/db肾脏的脂质堆积，同时增加了肾脏脂肪甘油三酯脂肪酶(ATGL)的表达。ATGL表达的改变与SIRT1表达增加和FOXO1去乙酰化相关。血管紧张素转换酶2水平在糖尿病肾病中的上调被血管紧张素转换酶1-7正常化。血管紧张素转换酶1-7治疗对糖尿病肾病具有肾脏保护作用，与减少氧化应激、炎症、纤维化和脂毒性有关。血管紧张素转换酶1-7是治疗糖尿病肾病的一种有前景的治疗方法。
The renin-angiotensin system, especially angiotensin II (ANG II), plays a key role in the development and progression of diabetic nephropathy. ANG 1-7 has counteracting effects on ANG II and is known to exert beneficial effects on diabetic nephropathy. We studied the mechanism of ANG 1-7induced beneficial effects on diabetic nephropathy in db/db mice. We administered ANG 1-7 (0.5 mg.kg(-1).day(-1)) or saline to 5-mo-old db/db mice for 28 days via implanted micro-osmotic pumps. ANG 1-7 treatment reduced kidney weight and ameliorated mesangial expansion and increased urinary albumin excretion, characteristic features of diabetic nephropathy, in db/db mice. ANG 1-7 decreased renal fibrosis in db/db mice, which correlated with dephosphorylation of the signal transducer and activator of transcription 3 (STAT3) pathway. ANG 1-7 treatment also suppressed the production of reactive oxygen species via attenuation of NADPH oxidase activity and reduced inflammation in perirenal adipose tissue. Furthermore, ANG 1-7 treatment decreased lipid accumulation in db/db kidneys, accompanied by increased expressions of renal adipose triglyceride lipase (ATGL). Alterations in ATGL expression correlated with increased SIRT1 expression and deacetylation of FOXO1. The upregulation of angiotensin-converting enzyme 2 levels in diabetic nephropathy was normalized by ANG 1-7. ANG 1-7 treatment exerts renoprotective effects on diabetic nephropathy, associated with reduction of oxidative stress, inflammation, fibrosis, and lipotoxicity. ANG 1-7 can represent a promising therapy for diabetic nephropathy.