Prevention of Angiotensin II-Mediated Renal Oxidative Stress, Inflammation, and Fibrosis by Angiotensin-Converting Enzyme 2

被引：182

作者：

Zhong, JiuChang

Guo, Danny

Chen, Christopher B.

Wang, Wang ^{[5
]}

Schuster, Manfred ^{[2
]}

Loibner, Hans ^{[2
]}

Penninger, Josef M. ^{[3
]}

Scholey, James W. ^{[4
]}

Kassiri, Zamaneh ^{[5
]}

Oudit, Gavin Y. ^{[1
,5
]}

机构：

[1] Univ Alberta, Mazankowski Alberta Heart Inst, Dept Med, Div Cardiol, Edmonton, AB T6G 2S2, Canada

[2] Apeiron Biol, Vienna, Austria

[3] Austrian Acad Sci, Inst Mol Biotechnol, A-1010 Vienna, Austria

[4] Univ Toronto, Dept Med, Div Nephrol, Toronto, ON, Canada

[5] Univ Alberta, Dept Physiol, Edmonton, AB T6G 2S2, Canada

来源：

HYPERTENSION | 2011年 / 57卷 / 02期

基金：

中国国家自然科学基金;

关键词：

angiotensin I; hypertension I; renal fibrosis; signal transduction; CHRONIC KIDNEY-DISEASE; PROXIMAL TUBULAR CELLS; INDUCED HYPERTENSION; PATHOLOGICAL HYPERTROPHY; ACE2; INJURY; EXPRESSION; MICE; DYSFUNCTION; INHIBITION;

D O I：

10.1161/HYPERTENSIONAHA.110.164244

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing angiotensin (Ang) II into Ang 1 to 7. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (1.5 mg/kg(-1)/d(-1)) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout (Ace2(-/y)) mice compared to wild-type mice. Expression of proinflammatory cytokines, interleukin-1 beta and chemokine (C-C motif) ligand 5, were increased in association with greater activation of extracellular-regulated kinase 1/2 and increase of protein kinase C-alpha levels. These changes were associated with increased expression of fibrosis-associated genes (alpha-smooth muscle actin, transforming growth factor-beta, procollagen type I alpha 1) and increased protein levels of collagen I with histological evidence of increased tubulointerstitial fibrosis. Ang II-infused wild-type mice were then treated with recombinant human ACE2 (2 mg/kg(-1)/d(-1), intraperitoneal). Daily treatment with recombinant human ACE2 reduced Ang II-induced pressor response and normalized renal Ang II levels and oxidative stress. These changes were associated with a suppression of Ang II-mediated activation of extracellular-regulated kinase 1/2 and protein kinase C pathway and Ang II-mediated renal fibrosis and T-lymphocyte-mediated inflammation. We conclude that loss of ACE2 enhances renal Ang II levels and Ang II-induced renal oxidative stress, resulting in greater renal injury, whereas recombinant human ACE2 prevents Ang II-induced hypertension, renal oxidative stress, and tubulointerstitial fibrosis. ACE2 is an important negative regulator of Ang II-induced renal disease and enhancing ACE2 action may have therapeutic potential for patients with kidney disease. (Hypertension. 2011;57:314-322.). Online Data Supplement

引用

页码：314 / U338

页数：18