Abstract: SA-PO0259
Tubular PPARδ-LCN2 Axis in AKI-Associated Remote Lung Injury
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Liu, Jing, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiang, Lei, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Cao, Hongdi, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Feng, Ganzhu, Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Dai, Chunsun, Center for Kidney Diseases, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background
Acute kidney injury (AKI) is frequently complicated by remote lung injury, yet the underlying mediators of kidney–lung crosstalk remain unclear. Lipocalin-2 (LCN2) is rapidly induced after AKI and may amplify systemic inflammation and tissue damage. We investigated whether tubular PPARδ regulates LCN2-mediated pulmonary endothelial injury following AKI.
Methods
Unilateral renal ischemia-reperfusion injury (uIRI) was induced in mice. LCN2 expression, pulmonary inflammation, and endothelial barrier injury were assessed. LCN2 function was tested by in vivo overexpression, recombinant LCN2 stimulation of pulmonary microvascular endothelial cells (PMVECs), and AKI serum with or without LCN2-neutralizing antibody. PPARδ regulation of LCN2 was evaluated by agonist activation, overexpression, knockdown, promoter prediction, and ChIP-qPCR. Tubular Pparδ knockout mice and single-cell RNA-seq were used.
Results
uIRI induced tubular injury with remote pulmonary inflammation, endothelial barrier disruption, and lung injury. LCN2 was elevated in injured kidneys and circulation after AKI. LCN2 overexpression aggravated pulmonary inflammation and endothelial barrier injury in vivo, while recombinant LCN2 directly increased inflammatory cytokines and disrupted junctional proteins in PMVECs. LCN2-neutralizing antibody attenuated AKI serum-induced endothelial injury, supporting LCN2 as a circulating effector. In tubular cells, oxidative stress reduced PPARδ expression. PPARδ activation or overexpression suppressed LCN2 expression/release, whereas PPARδ knockdown increased LCN2 secretion. ChIP-qPCR confirmed PPARδ enrichment at the Lcn2 promoter. In vivo, a PPARδ agonist reduced renal LCN2 and tubular injury after IRI, while tubular Pparδ deletion aggravated AKI and remote lung injury and increased circulating LCN2. Single-cell RNA-seq showed that Pparδ deletion upregulated pathways linked to lipid metabolism, ferroptosis, and NF-κB signaling.
Conclusion
LCN2 mediates AKI-induced pulmonary endothelial injury. Tubular PPARδ negatively regulates LCN2 via promoter-associated transcriptional control and limits inflammatory-metabolic remodeling after AKI. Targeting the PPARδ–LCN2 axis may represent a novel strategy to prevent AKI-associated remote lung injury.
Funding
- Government Support – Non-U.S.