Abstract: SA-PO0170
Tubular-Specific EphB2 Deletion or Inhibition Mitigates Ischemia-Reperfusion-Induced Kidney Fibrosis
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: 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
- Bell, Frank T, 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 tyrosine kinase signaling is markedly activated in the kidneys of both CKD animal models and patients. Global deletion of EphB2 confers protection against ischemia-reperfusion (IR)-induced kidney injury and fibrosis. However, its specific cellular location and function in the kidney remains unclear.
Methods
We examined the cellular distribution of EphB2 and generated tubular-specific EphB2 knockout (KO) mice. Additionally, we utilized a selective EphB2 inhibitor to assess the role of tubular EphB2 in a unilateral renal IR mouse model.
Results
Elevated EphB2 expression was primarily localized to renal tubular cells-particularly in the distal convoluted tubule (DCT) and collecting duct (CD)- and vascular smooth muscle cells (VSMCs). In a severe unilateral IR model induced by 35 minutes of ischemia, with removal of the controlateral kidney one day before termination, EphB2 levels in the injured kidney were significantly upregulated- by 2.8-fold at day 3 and 8.5-fold at day 14 post-injury- correlating with the severity of tubulointerstitial fibrosis. In Pax8-Lc1-cre-driven tubular-specific EphB2KO mice, doxycycline-induced deletion of EphB2 across the nephron significantly improved kidney function and reduced tubular injury, as indicated by decreased plasma BUN and Cr levels, lowered kidney Kim1 and NGAL mRNA expression, and reduced Kim1 protein levels at day 14 post-injury. These mice also exhibited markedly reduced tubulointerstitial inflammation and fibrosis, as demonstrated by Masson’s Trichrome, a-SMA, and F4/80 staining, along with downregulation of fibrotic markers (fibronectin, a-SMA, and vimentin). Notably, expression of inflammatory and senescence-associated genes- NF-kBp65, Nox2, TGFß1, Wisp1, p21, and p16- was restored to near-normal levels in tubular EphB2 KO mice. Similar protective effects were observed in wild-type mice treated for 14 days post-IR with 3511-I, a novel small-molecule EphB2 inhibitor.
Conclusion
Tubular-specific genetic deletion or pharmacological inhibition of EphB2 attenuates IR-induced kidney injury and fibrosis, through promoting tubular repair and suppressing sustained inflammatory signaling.
Funding
- NIDDK Support