Abstract: FR-PO0672
Deflating the Disease: VEGFR2 Blockade as a Novel Therapeutic Strategy in PKD
Session Information
- Cystic Kidney Diseases: Basic and Translational Research
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Nuñez-Gonzalez, Laura, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Tejedor, Lucia, Universidad Autonoma de Madrid, Madrid, Community of Madrid, Spain
- Ouro, Alberto, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Pereira Hernández, María, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Castro Mosquera, Monica, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Barcia de la Iglesia, Ana, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Martínez Pulleiro, Raquel, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Cordido, Adrian, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
- Ortiz, Alberto, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Community of Madrid, Spain
- Ruiz-Ortega, Marta, Universidad Autonoma de Madrid, Madrid, Community of Madrid, Spain
- Garcia-Gonzalez, Miguel A., Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
Group or Team Name
- RICORS 2040.
Background
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by progressive renal cyst formation and extrarenal manifestations such as hepatic cysts. It is primarily caused by mutations in PKD1 and PKD2. Despite advances in understanding its genetic basis, the molecular mechanisms driving cystogenesis remain unclear. The Gremlin-NOTCH-VEGFR2 signaling axis, known to be activated in chronic kidney diseases, may play a role in ADPKD progression. This study investigates the involvement of this pathway and evaluates VEGFR2 inhibition as a therapeutic strategy.
Methods
We analyzed the expression of Gremlin, NOTCH1, and VEGFR2 pathway in human ADPKD samples and in an orthologous mouse model (B6.Pkd1flox/flox;Tam-Cre). VEGFR2 inhibition was tested using Semaxinib in both rapidly and slowly progressive models. Disease progression was monitored by MRI and blood analysis. After, molecular validation included western blot, immunohistochemistry, and quantitative PCR.
Results
We identified a consistent upregulation of the Gremlin-NOTCH-VEGFR2 signaling axis in tissues, urine, and cystic fluid from patients with autosomal dominant polycystic kidney disease (ADPKD). In a rapid disease progression model, short-term treatment with the VEGFR2 inhibitor semaxinib led to improved renal function, evidenced by reduced blood urea nitrogen (BUN) levels and a significant decrease in cystic burden. Semaxinib also attenuated renal inflammation and fibrosis, as indicated by the downregulation of pro-inflammatory and fibrotic markers. In a slow progression model, long-term semaxinib administration resulted in reduced total kidney volume and slowed cyst expansion, as confirmed by MRI. Mechanistically, semaxinib suppressed VEGFR2 signaling and its downstream effectors, while partially restoring the cystic phenotype, suggesting a modulatory effect on key pathogenic pathways of ADPKD.
Conclusion
Our findings highlight the pathological activation of the Gremlin/VEGFR2 signaling pathway in ADPKD and demonstrate the therapeutic promise of VEGFR2 inhibition. These results provide a compelling rationale for further investigation of this pathway as a target for disease-modifying therapies in PKD.