Abstract: FR-PO1192
Novel EphB2 Signaling Promotes Renal Inflammation and Fibrotic Remodeling in Deoxycorticosterone Acetate/Angiotensin II-Induced CKD
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Wang, Zhou, University of Utah Health, Salt Lake City, Utah, United States
- Zhuang, Lili, University of Utah Health, Salt Lake City, Utah, United States
- Liu, Wenjin, University of Utah Health, Salt Lake City, Utah, United States
- Li, Davey, University of Utah Health, Salt Lake City, Utah, United States
- Henkemeyer, Mark, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States
Background
EphB2 receptor expression is elevated in the kidneys of patients with chronic kidney disease (CKD), but its role in CKD pathogenesis remains unclear. This study investigates the contribution of EphB2 signaling to progressive kidney injury in a mouse model of CKD induced by deoxycorticosterone-acetate-salt (DOCA) and angiotensin II (AII) infusion.
Methods
Male wild-type (WT) and EphB2 knockout (KO) mice (12 to 20 weeks old) underwent uninephrectomy (UNx), followed one week later by 3 weeks of DOCA+AII infusion with 1% NaCl in drinking water. In the treatment group, DOCA+AII-infused WT mice treated with or without A20, a novel small MW EphB2 inhibitor (20mg/kg/day, intraperitoneally). Control mice received saline injections after UNx without DOCA or AII.
Results
DOCA+AII infusion significantly increased renal EphB2 receptor and its ligand ephrin B2 (EfnB2) expression by 5.4 and 1.8-fold, respectively. Elevated EphB2 localized primarily to tubular and vessel smooth muscle cells, while EfnB2 was present in both tubular and glomerular podocytes. Despite similar blood pressure levels were found between WT and EphB2 KO mice (SBP ≈167 mmHg, P<0.05, determined by either the telemetry or the tail-cuff measurement) after DOCA+AII infusion, EphB2 KO mice showed marked improvements, including reduced albuminuria and significant reductions in impaired renal function, tubular injury score, glomerular and tubulointerstitial fibrosis, macrophage infiltration by 50.3%, 45.1%, 49.4% and 65% respectively (P<0.01). These effects were accompanied by reduced EfnB2 expression, attenuated tubular injury markers (lower KIM-1, NGAL and OPN expression), and decreased renal inflammation, oxidative stress, and fibrosis markers (NF-kB-p65, Nox2, TGFß1 and Wisp1). Treatment with A20 provided similar renal protection including arresting the progression of albuminuria, without affecting blood pressure.
Conclusion
Our findings suggest that EphB2 signaling is overactivated in DOCA+AII induced kidney injury and contributes to albuminuria, inflammation, oxidative stress, and fibrosis. Targeting EphB2 may offer a promising therapeutic approach for CKD.
Funding
- NIDDK Support