期刊
KIDNEY INTERNATIONAL
卷 102, 期 4, 页码 780-797出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2022.06.026
关键词
chronic kidney disease; endothelium; fibrosis; macrophage; chemokine
资金
- Ministry of Science and Technology [106-2314-B-002-161-MY3, 108-2314-B-002-078-MY3, 110-2314-B-002-208, 111-2314-B-002-037]
- National Taiwan University Hospital [108-S4187, 109-S4478, 110-S4844, 111-X0026, 111-S0118, 108-T16, 109-T16, 110-S4837, 111-S0014, 111-TMU022]
- Mrs. Hsiu-Chin Lee Kidney Research Foundation
- National Taiwan University College of Medicine [NSCCMOH-131-43, 145-72]
- National Taiwan University [NTU-CC-110L893304, 111L892704]
- Taiwan Health Foundation
Plasma levels of angiopoietin-2 are elevated in patients with chronic kidney disease (CKD), and this increase is associated with the development of kidney failure. Overexpression of angiopoietin-1 in mouse models of progressive kidney disease attenuates macrophage infiltration, endothelial cell apoptosis, microvascular rarefaction, and fibrosis. Additionally, an angiopoietin-2 inhibitor has inhibitory effects on macrophage infiltration, microvascular rarefaction, and fibrosis in these models.
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.
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