Cell-Specific Roles of Angiopoietin-2 in CKD

Abstract

Background: CKD is driven by inflammation, vascular dysfunction, and fibrosis, with emerging evidence implicating angiopoietin-2 as a key mediator. While angiopoietin-2 is produced by endothelial cells and upregulated in injured tubular epithelial cells (TECs), the distinct contributions of endothelial cell- and TEC-derived angiopoietin-2 remain unclear. This study defines the cell type-specific roles of angiopoietin-2 in CKD pathogenesis.

Methods: We examined kidney transcriptomes and outcomes from the Taipei Renal Transcriptomics and Outcomes Investigation cohort, with fibrosis assessed by histology and RNA sequencing. Global, endothelial cell-specific, and TEC-specific angiopoietin-2 knockout mice were subjected to experimental CKD. Kidney injury, inflammation, vascular changes, and fibrosis were evaluated using histological, molecular, and imaging analyses.

Results: In CKD patients, elevated kidney ANGPT2 mRNA was associated with lower estimated glomerular filtration rate, greater kidney fibrosis, and adverse kidney outcomes. Global deletion of angiopoietin-2 in mice preserved kidney function and reduced inflammation, vascular rarefaction, and fibrosis during CKD progression-induced by an adenine diet. Transcriptomic profiling revealed suppression of pro-inflammatory and pro-fibrotic pathways, and enhancement of peroxisomal lipid metabolism. Endothelial cell-specific deletion of angiopoietin-2 attenuated early inflammatory signaling and endothelial activation but failed to prevent late-stage vascular rarefaction and fibrosis. In contrast, TEC-specific deletion preserved kidney function and reduced fibrotic and vascular injury in late-stage CKD, without impacting early inflammation and endothelial activation. Mechanistically, angiopoietin-2 promoted macrophage recruitment and matrix deposition through cell-specific pathways, without directly altering metabolism of TECs.

Conclusions: This study identifies angiopoietin-2's contribution to CKD pathogenesis through distinct roles of endothelial and tubular epithelial sources. Endothelial deletion mainly reduced early inflammation, while tubular epithelial deletion limited progressive injury and advanced fibrosis.