Abstract: SA-PO1178
Inhibition of Lymphangiogenesis Exacerbates Cisplatin Nephrotoxicity
Session Information
- NIDDK KUH Summer Undergraduate Research Program Posters
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onco-Nephrology
- 1500 Onco-Nephrology
Author
Group or Team Name
- Elisa Farrell. The University of Alabama at Birmingham, Birmingham, AL.
Background
The lymphatic system is a complex network of channels responsible for lipid transport, fluid homeostasis, and immune response. The creation of new lymphatic vessels, or lymphangiogenesis, occurs primarily in development, though studies show that vascular endothelial growth factor C or D (VEGF-C or -D) stimulate de novo lymphangiogenesis in disease through interaction with their receptor, VEGFR-3. We have previously shown this process to occur following acute kidney injury (AKI). However, no previous studies have evaluated whether lymphangiogenesis is beneficial or harmful in AKI.
Methods
This study utilized MAZ51 [10 mg/kg bodyweight in DMSO intraperitoneally (i.p.)], a VEGFR-3 kinase inhibitor, to block lymphangiogenesis in a model of cisplatin nephrotoxicity (20 mg/kg bodyweight in saline i.p.). Mice were harvested 3 days post-cisplatin injection. Biomarkers of renal function, injury, inflammation, and lymphangiogenesis were measured.
Results
We report that inhibition of lymphangiogenesis exacerbates cisplatin nephrotoxicity. MAZ51 treated mice experienced significantly worsened kidney function, measured by elevated serum creatinine (1.1 ± 0.3 vs. 0.31 ± 0.05 mg/dL), decreased glomerular filtration rate (11.9 ± 3.9 vs. 80.6 ± 20.6 μl/min), and increased serum cystatin C. MAZ51 mice also experienced significantly increased expression of intrarenal KIM-1, compared with cisplatin alone treated mice. We also observed a significant rise in intrarenal inflammatory markers (Csf1, Ccl2, Tnfα) and heme oxygenase-1 (Hmox1), as well as increased cell death, compared with cisplatin alone controls.
Conclusion
Taken together, our study describes a novel role for lymphangiogenesis as an adaptive response following cisplatin AKI and may be a promising target for therapeutic intervention.