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

• DOI: 10.1016/j.kint.2022.06.026
• Publication Date: 2022-08-04T08:26:10Z
• Authors: 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; Shuei-Liong Lin
• Keywords: 0301 basic medicine; Microvascular Rarefaction; Endothelial Cells; Apoptosis; Kidney; Ligands; Fibrosis; 3. Good health; Angiopoietin-2; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Angiopoietin-1; Animals; Humans; Chemokines; Renal Insufficiency, Chronic; Chemokine CCL2

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.