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

Targeting angiopoietin-2 as a novel treatment option for kidney fibrosis

“…ANGPT2 was found to dose-dependently increase chemokine (CC motif) ligand 2 (CCL2) expression. 8 However, this ANGPT2induced increase in CCL2 was negated when these primary ECs were cocultured with ANGPT1 or when endothelial TIE2 expression (which was expressed on CD31 þ ECs) was knocked down by small, interfering RNA, 8 confirming the role of TIE2 in the induction of CCL2 by ANGPT2. In addition, CCL2 neutralization with the use of an anti-CCL2 antibody abrogated the migration of RAW264.7 macrophages, which suggested that ANGPT2-induced endothelial CCL2 activity was promoting macrophage infiltration (inflammation) in a paracrine manner.…”

“…7 Consistent with this, circulating and tubular EC levels of ANGPT2 were also increased in mice subjected to 5/6 nephrectomy, in which ANGPT2 was found to contribute to arterial stiffness through its ability to promote aortic macrophage infiltration, transforming growth factor-b1 expression and interstitial collagen deposition (the basis of interstitial fibrosis). 7 With this in mind, Chang et al 8 (this issue) further investigated the mechanisms by which ANGPT2 mediated its detrimental effects on CKD progression and also evaluated the extent to which the therapeutic inhibition of ANGPT2 could attenuate kidney inflammation, EC apoptosis, and fibrosis in murine models of progressive kidney disease. In a cohort of 319 patients with CKD, the investigators confirmed that plasma ANGPT2 levels and the ANGPT2:ANGPT1 ratio were positively associated with the risk of kidney failure, as determined by patients with later stages of CKD having higher serum phosphate and uric acid, intact parathyroid hormone, and lower albumin, calcium, and hemoglobin levels.…”

“…In a cohort of 319 patients with CKD, the investigators confirmed that plasma ANGPT2 levels and the ANGPT2:ANGPT1 ratio were positively associated with the risk of kidney failure, as determined by patients with later stages of CKD having higher serum phosphate and uric acid, intact parathyroid hormone, and lower albumin, calcium, and hemoglobin levels. 8 Based on this, the effects of recombinant ANGPT2 on primary kidney ECs, which were isolated from mice with unilateral ureteric obstruction (UUO) or unilateral ischemia reperfusion injury and fluorescence-activated cell sortingsorted for being TIE2 þ /CD31 þ / CD11b(macrophage, granulocyte, and natural killer cell) À /platelet-derived growth factor (PDGF) receptor-a (PDGFRa) À , were evaluated. ANGPT2 was found to dose-dependently increase chemokine (CC motif) ligand 2 (CCL2) expression.…”

“…In addition, CCL2 neutralization with the use of an anti-CCL2 antibody abrogated the migration of RAW264.7 macrophages, which suggested that ANGPT2-induced endothelial CCL2 activity was promoting macrophage infiltration (inflammation) in a paracrine manner. 8 As macrophage infiltration might be a possible mechanism that leads to capillary rarefaction, the effects of ANGPT2 on measures of EC apoptosis were then measured in primary kidney ECs. ANGPT2 alone did not alter the expression of Akt phosphorylation, cleaved caspase-3, or annexin V in ECs.…”

“…The therapeutic targeting of ANGPT2 was demonstrated via the use of ANGPT1 (in the form of transgenic mice that overexpressed human ANGPT1) or with the specific ANGPT2 inhibitor, L1-10. 8 As part of their study, Chang et al 8 used diphtheria toxin activation of double transgenic mice, which expressed Pax8 reverse tetracycline-dependent transactivator (Pax8-rtTA) in all proximal and distal tubules and the entire collecting duct system under the control of the mouse Pax8 promoter with pTRE-hANGPT1 mice, which expressed human ANGPT1 in cells expressing rTA. When subjected to UUO or unilateral ischemia reperfusion injury, mice overexpressing human ANGPT1 had reduced kidney expression of endothelial CCL2, various proinflammatory (CCL17, CCL22, C-C chemokine receptor type 2, and C-X3-C motif receptor 1) and profibrotic (transforming growth factor-b1, PDGF, and ACTA2) genes, macrophage infiltration, EC apoptosis, microvascular rarefaction, and interstitial fibrosis.…”