Abstract: TH-PO464
Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Blockade as New Therapeutic Opportunity for Polycystic Kidney Disease
Session Information
- Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
October 24, 2024 | 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: Cystic
Authors
- Nuñez-Gonzalez, Laura, Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
- Tejedor, Lucia, Universidad Autonoma de Madrid, Madrid, Spain
- Pereira Hernández, María, Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
- Barcia de la Iglesia, Ana, Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
- Cordido, Adrian, Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
- Garcia-Gonzalez, Miguel A., Instituto de Investigacion Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
- Ruiz-Ortega, Marta, Universidad Autonoma de Madrid, Madrid, Spain
Background
Polycystic Kidney Disease (PKD) encompasses a group of genetic disorders characterized by the presence of multiple cysts in the renal parenchyma, alongside extrarenal manifestations such as hepatic cysts, termed Polycystic Liver Disease (PLD). Autosomal Dominant Polycystic Kidney Disease (ADPKD), the dominantly inherited form, arises from mutations in genes PKD1 and PKD2. Despite extensive research efforts, the precise mechanism underlying cystogenesis in PKD remains elusive. This study focuses on investigating the role of NOTCH signaling in ADPKD, given its documented activation in various progressive kidney diseases. Cystogenesis progression is marked by pronounced inflammation, with interstitial fibroblasts and macrophage polarization releasing chemokines, cytokines, and growth factors. Additionally, GREMLIN (one of the key mediators of NOTCH pathway) has emerged as a key mediator of chronic kidney disease in preclinical studies, with urinary levels proposed as potential biomarkers for renal diseases.
Methods
To assess the involvement of the Gremlin-VEGFR2 signaling pathway in cystic disease, we examined the expression of pathway proteins in both human samples and an orthologous murine model of ADPKD. Additionally, we validated the inhibition of VEGFR2 as a potential therapeutic strategy using an orthologous rapid progressive mouse model: B6.Pkd1 cko/cko TamCre.
Results
Our findings revealed upregulation of Gremlin/VEGFR2 pathway proteins in ADPKD, evident through transcriptomic and proteomic overexpression in ADPKD mouse kidney tissues, as well as in urine and cystic fluid from ADPKD patients.
Treatment with Semaxinib, a specific VEGFR2 inhibitor, yielded beneficial effects in a short term-treatment in a rapid progressive ADPKD mouse model, including significant improvement in renal function (measured by BUN levels) as well as a significant reductions in cystic area.
Conclusion
This study sheds light on the altered role of the Gremlin/VEGFR2 pathway in cystogenesis and cyst growth progression in ADPKD. Moreover, the efficacy of a VEGFR2 inhibitor as demonstrated in a preclinical ADPKD model suggests a promising therapeutic avenue for PKD diseases.