https://scholars.lib.ntu.edu.tw/handle/123456789/624355
標題: | Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells | 作者: | FAN-CHI CHANG Liu, Chia-Hao Luo, An-Jie TAO-MIN HUANG Tsai, Ming-Hsuan Chen, Yu-Jhen CHUN-FU LAI CHIH-KANG CHIANG Lin, Tzu-Hung WEN-CHIH CHIANG YUNG-MING CHEN Chu, Tzong-Shinn SHUEI-LIONG LIN |
關鍵字: | chemokine; chronic kidney disease; endothelium; fibrosis; macrophage | 公開日期: | 十月-2022 | 卷: | 102 | 期: | 4 | 來源出版物: | Kidney international | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/624355 | ISSN: | 00852538 | DOI: | 10.1016/j.kint.2022.06.026 |
顯示於: | 醫學系 |
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