Cell-Specific Roles of Angiopoietin-2 in CKD

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KEY POINTS: Global deletion of angiopoietin-2 protected against the progression of CKD. Endothelial cell-derived angiopoietin-2 drove early inflammation by promoting endothelial activation. Tubular epithelial cell-derived angiopoietin-2 contributed to functional decline and kidney fibrosis in advanced CKD. 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-derived 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 histologic, molecular, and imaging analyses. RESULTS: In patients with CKD, 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 proinflammatory and profibrotic 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. By 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.

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