1. Angiopoietin-2 inhibition attenuates kidney fibrosis by hindering chemokine C-C motif ligand 2 expression and apoptosis of endothelial cells
- Author
-
Fan-Chi Chang, Chia-Hao Liu, An-Jie Luo, Thomas Tao-Min Huang, Ming-Hsuan Tsai, Yu-Jhen Chen, Chun-Fu Lai, Chih-Kang Chiang, Tzu-Hung Lin, Wen-Chih Chiang, Yung-Ming Chen, Tzong-Shinn Chu, and Shuei-Liong Lin
- Subjects
Microvascular Rarefaction ,Endothelial Cells ,Apoptosis ,Kidney ,Ligands ,Fibrosis ,Angiopoietin-2 ,Mice, Inbred C57BL ,Mice ,Nephrology ,Angiopoietin-1 ,Animals ,Humans ,Chemokines ,Renal Insufficiency, Chronic ,Chemokine CCL2 - Abstract
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.
- Published
- 2022