Abstract: SA-PO0138
CCN2 Deficiency Boosts Glycolytic Metabolic Reprogramming in the Kidneys Following Ischemia-Reperfusion Injury
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
- Ruiz-Ortega, Marta, Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz,Universidad Autónoma de Madrid, Madrid, Spain
- Cuevas-Delgado, Paula, Universidad CEU San Pablo, Madrid, Community of Madrid, Spain
- Tejedor, Lucia, Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz,Universidad Autónoma de Madrid, Madrid, Spain
- Rodrigues Díez, Raúl R., Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz,Universidad Autónoma de Madrid, Madrid, Spain
- Marchant, Vanessa A, Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz,Universidad Autónoma de Madrid, Madrid, Spain
- Salguero, Elena Flores, Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz,Universidad Autónoma de Madrid, Madrid, Spain
- Barbas, Coral, Universidad CEU San Pablo, Madrid, Community of Madrid, Spain
- Milhano Santos, Fátima, Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz,Universidad Autónoma de Madrid, Madrid, Spain
Background
Renal ischemia–reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI). IRI is characterized by transient oxygen and nutrient deprivation, which triggers metabolic reprogramming in the kidney and AKI. Cellular communication network factor 2 (CCN2) has been implicated in renal damage by regulating necroptosis, inflammation, and fibrosis. Recent studies suggest that CCN2 may act as a metabolic regulator in chondrocytes, but there is no data on kidney cells. Building on our previous findings that targeting CCN2 reduces renal injury, we hypothesized that CCN2 deficiency might promote a protective metabolic shift following IRI.
Methods
To evaluate this hypothesis, we performed a combined untargeted lipidomics and targeted metabolomics analysis focusing on glycolysis and the pentose phosphate pathway in renal tissues from wild-type (WT) and CCN2-deficient (KO-CCN2) mice subjected to IRI or sham surgery. Key metabolic enzymes and damage markers were evaluated by qPCR and kidney function was assessed through serum markers.
Results
IRI induced changes in the levels of 84 and 82 lipids in WT and KO-CCN2 mice, respectively. However, only 3 metabolites changed significantly between the KO-CCN2+IRI and WT+IRI groups. In contrast, KO-CCN2+IRI kidneys showed a marked increase in glycolytic intermediates phosphoenolpyruvate and fructose-1,6-bisphosphate, along with upregulation of Hk1, Pkm, HIF-1α, and Nfe2l2. While global lipid profiles remained unaffected, CCN2 levels negatively correlated with lipid metabolism enzymes (e.g., Acadm) and positively with kidney injury and function markers. These trends were confirmed in a folic acid nephropathy model, where similar correlations were observed, although no enhancement of glycolytic flux was detected.
Conclusion
CCN2 deficiency does not significantly affect lipid metabolism, but it does promote a compensatory increase in glycolysis, potentially mediated by HIF-1α and Nfe2l2. This metabolic adaptation may underlie the protective phenotype previously observed in CCN2-KO mice. The consistent correlation of CCN2 with renal injury biomarkers reinforces our previous studies, positioning CCN2 as a potential therapeutic target in AKI.
Funding
- Government Support – Non-U.S.