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

Kidney Int. 2022 Oct;102(4):780-797. doi: 10.1016/j.kint.2022.06.026. Epub 2022 Aug 4.


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.

Keywords: chemokine; chronic kidney disease; endothelium; fibrosis; macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-1
  • Angiopoietin-2 / metabolism
  • Animals
  • Apoptosis
  • Chemokine CCL2 / metabolism
  • Chemokines / metabolism
  • Endothelial Cells / pathology
  • Fibrosis
  • Humans
  • Kidney / pathology
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Microvascular Rarefaction* / metabolism
  • Microvascular Rarefaction* / pathology
  • Renal Insufficiency, Chronic* / pathology


  • Angiopoietin-1
  • Angiopoietin-2
  • Chemokine CCL2
  • Chemokines
  • Ligands