Abstract: TH-PO1141
OX40L Exacerbates Tubular Injury and Interstitial Inflammation in AKI-to-CKD Transition Through GSK3α
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Yang, Kexin, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China
- Duan, Shaobin, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China
- Sun, Lin, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China
- Liu, Fu-You, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China
- Xiao, Li, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China
Background
The incidence of acute kidney injury (AKI) has been steadily increasing recently, with long-term consequences including chronic kidney disease (CKD) and end-stage renal disease. Inflammation is recognized as a critical driver in AKI-to-CKD, promoting interstitial fibrosis. Tumor necrosis factor ligand superfamily member 4 (TNFSF4), also known as OX40L, functions as a co-stimulatory ligand for T cells and plays a critical role in inflammation. However, the role and mechanisms of OX40L-mediated inflammation in AKI-to-CKD remain unclear.
Methods
The expression of OX40L in tubular cells in patients with renal fibrosis and AKI-to-CKD animal models was evaluated using immunoblotting, real-time PCR, and immunostaining. Proximal tubular cell-specific Tnfsf4 knockout mice were generated to investigate the role of OX40L in AKI-to-CKD. In vitro, the effects of OX40L were assessed by OX40L siRNA or overexpression plasmids. Furthermore, immunoprecipitation-mass spectrometry (IP-MS) and co-inmunoprecipitation (Co-IP) was employed to identify OX40L-interacting proteins aiming to elucidate its functional role in the AKI-to-CKD transition.
Results
We identified a significant upregulation of OX40L expression in tubular cells in patients with renal fibrosis and AKI-to-CKD animals. Elevated OX40L levels were positively correlated with tubular interstitial injury and negatively correlated with eGFR. Proximal tubule-specific knockout of OX40L attenuated tubular injury, interstitial fibrosis and renal inflammation in AKI-to-CKD mice induced by ischemia-reperfusion injury or repeated low-dose cisplatin. In vitro, OX40L overexpression markedly enhanced inflammation, apoptosis, and extracellular matrix (ECM) production in tubular cells exposed to TGF-β1 or chronic hypoxia. Mechanistically, IP-MS analysis and Co-IP suggested a potential interaction between OX40L and glycogen synthase kinase-3α (GSK3α). Silencing OX40L aggravated tubular inflammation, injury, and ECM accumulation, effects that were partially reversed by GSK3α knockdown. More importantly, OX40L overexpression markedly attenuates the ubiquitination of GSK3α in HEK293T.
Conclusion
These results reveal that OX40L exacerbates tubular injury and interstitial inflammation in AKI-to-CKD transition through GSK3α, which may offer a novel therapeutic strategy to prevent or slow the progression of AKI-to CKD.
Funding
- Government Support – Non-U.S.