Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome

被引：33

作者：

Bae, Eun Hui ^{[1
,2
,3
]}

Fang, Fei ^{[1
,2
]}

Williams, Vanessa R. ^{[1
,2
]}

Konvalinka, Ana ^{[1
,2
,4
,5
]}

Zhou, Xiaohua ^{[1
,2
]}

Patel, Vaibhav B. ^{[6
]}

Song, Xuewen ^{[5
,7
,8
]}

John, Rohan ^{[5
,9
]}

Oudit, Gavin Y. ^{[6
]}

Pei, York ^{[5
,7
,8
]}

Scholey, James W. ^{[1
,2
,4
,5
]}

机构：

[1] Univ Toronto, Dept Med, Toronto, ON, Canada

[2] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[3] Chonnam Natl Univ, Sch Med, Dept Internal Med, Gwangju, South Korea

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

[5] Univ Toronto, 1 Kings Coll Circle,Room 7326, Toronto, ON M5S 1A8, Canada

[6] Univ Alberta, Dept Med, Div Cardiol, Edmonton, AB, Canada

[7] Univ Hlth Network, Div Nephrol, Toronto, ON, Canada

[8] Univ Hlth Network, Div Genom Med, Toronto, ON, Canada

[9] Univ Hlth Network, Dept Pathol, Toronto, ON, Canada

来源：

KIDNEY INTERNATIONAL | 2017年 / 91卷 / 06期

基金：

加拿大健康研究院;

关键词：

Alport syndrome; angiotensin-converting enzyme 2; renal fibrosis; renin-angiotensin system; TNF alpha-converting enzyme; BASEMENT-MEMBRANE NEPHROPATHY; PROXIMAL TUBULAR CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; CREATININE CLEARANCE; OXIDATIVE STRESS; RENAL FIBROSIS; BLOOD-PRESSURE; MICE; DISEASE; PROGRESSION;

D O I：

10.1016/j.kint.2016.12.022

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase in the renin-angiotensin system that catalyzes the breakdown of angiotensin II to angiotensin 1-7. We have reported that ACE2 expression in the kidney is reduced in experimental Alport syndrome but the impact of this finding on disease progression has not been studied. Accordingly, we evaluated effects of murine recombinant ACE2 treatment in Col4a3 knockout mice, a model of Alport syndrome characterized by proteinuria and progressive renal injury. Murine recombinant ACE2 (0.5 mg/kg/day) was administered from four to seven weeks of age via osmotic mini-pump. Pathological changes were attenuated by murine recombinant ACE2 treatment which ameliorated kidney fibrosis as shown by decreased expression of COL1 alpha 1 mRNA, less accumulation of extracellular matrix proteins, and inhibition of transforming growth factor-beta signaling. Further, increases in proinflammatory cytokine expression, macrophage infiltration, inflammatory signaling pathway activation, and heme oxygenase-1 levels in Col4a3 knockout mice were also reduced by murine recombinant ACE2 treatment. Lastly, murine recombinant ACE2 influenced the turnover of renal ACE2, as it suppressed the expression of tumor necrosis factor-alpha converting enzyme, a negative regulator of ACE2. Thus, treatment with exogenous ACE2 alters angiotensin peptide metabolism in the kidneys of Co14a3 knockout mice and attenuates the progression of Alport syndrome nephropathy.

引用

页码：1347 / 1361

页数：15

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