Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells

被引:34
作者
Chang, Fan-Chi [1 ]
Liu, Chia-Hao [2 ]
Luo, An-Jie [2 ]
Huang, Thomas Tao-Min [1 ]
Tsai, Ming-Hsuan [2 ]
Chen, Yu-Jhen [2 ]
Lai, Chun-Fu [1 ]
Chiang, Chih-Kang [1 ,3 ,4 ]
Lin, Tzu-Hung [5 ]
Chiang, Wen-Chih [1 ]
Chen, Yung-Ming [1 ]
Chu, Tzong-Shinn [1 ]
Lin, Shuei-Liong [1 ,2 ,3 ,6 ]
机构
[1] Natl Taiwan Univ Hosp, Div Renal, Dept Internal Med, Taipei, Taiwan
[2] Natl Taiwan Univ, Grad Inst Physiol, Coll Med, Taipei, Taiwan
[3] Natl Taiwan Univ Hosp, Dept Integrated Diagnost & Therapeut, Taipei, Taiwan
[4] Natl Taiwan Univ, Grad Inst Toxicol, Coll Med, Taipei, Taiwan
[5] Ind Technol Res Inst, Mat & Chem Res Labs, Zhudong, Taiwan
[6] Natl Taiwan Univ, Res Ctr Dev Biol & Regenerat Med, Taipei, Taiwan
关键词
chronic kidney disease; endothelium; fibrosis; macrophage; chemokine; RENAL FIBROSIS; GROWTH-FACTOR; ANGIOGENESIS; INFLAMMATION; DEATH; RAREFACTION; STABILIZES; INDUCTION; HYPOXIA; TIE2;
D O I
10.1016/j.kint.2022.06.026
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
Plasma levels of angiopoietin-2 are increased in patients with chronic kidney disease (CKD). Moreover, mouse models of progressive kidney disease also demonstrate increased angiopoietin-2 in both plasmas and kidneys. The role of dysregulated angiopoietins in the progression of kidney disease has not been thoroughly investigated. Here, we found in a cohort of 319 patients with CKD that plasma angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratios were positively associated with the development of kidney failure. In mice with progressive kidney disease induced by either ureteral obstruction or ischemia-reperfusion injury, overexpression of human angiopoietin-1 in the kidney tubules not only reduced macrophage infiltration in the initial stage post-injury but also attenuated endothelial cell apoptosis, microvascular rarefaction, and fibrosis in the advanced disease stage. Notably, angiopoietin-1 attenuated chemokine C-C motif ligand 2 (CCL2) expression in the endothelial cells of the fibrosing kidneys, and these protective effects led to attenuation of functional impairment. Mechanistically, angiopoietin-1 reduced CCL2-activated macrophage migration and protected endothelial cells against cell apoptosis induced by angiopoietin-2 and Wnt ligands. Based on this, we applied L1-10, an angiopoietin-2 inhibitor, to the mouse models of progressive kidney disease and found inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis. Thus, we defined the detrimental impact of increased angiopoietin-2 on kidney survival of patients with CKD which appears highlighted by angiopoietin-2 induced endothelial CCL2-activated macrophage infiltration and endothelial cell apoptosis in their kidneys undergoing fibrosis.
引用
收藏
页码:780 / 797
页数:18
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