VEGFR3 tyrosine kinase inhibition aggravates cisplatin nephrotoxicity.

Expansion of renal lymphatic networks, or lymphangiogenesis (LA) is well-recognized during development, and is now being implicated in kidney diseases. Though LA is associated with multiple pathological conditions, very little is known about its role in acute kidney injury (AKI). The purpose of this study was to evaluate the role of LA in a model of cisplatin-induced nephrotoxicity. LA is predominately regulated by VEGF-C and VEGF-D, ligands that exert their function through their cognate receptor VEGFR3. We demonstrate the use of MAZ51, a selective VEGFR3 inhibitor, which caused significantly worse structural and functional kidney damage in cisplatin nephrotoxicity. Apoptotic cell death and inflammation were also increased in the MAZ51 treated animals compared to vehicle-treated animals following cisplatin administration. Notably, MAZ51 caused significant upregulation of intrarenal phospho-NF-kB, phospho-JNK, and IL-6. Cisplatin nephrotoxicity is associated with vascular congestion due to endothelial dysfunction. Using three-dimensional tissue cytometry, a novel approach to explore lymphatics in the kidney, we detected significant vascular autofluorescence attributed to erythrocytes in cisplatin alone treated animals. Interestingly, no such congestion was detected in MAZ51 treated animals. We found increased renal vascular damage in MAZ51 treated animals, whereby MAZ51 caused a modest decrease in endothelial markers Emcn and vWF, with a modest increase in VEGFR2. Our findings identify a protective role for de novo LA in cisplatin nephrotoxicity and provide a rationale for the development of therapeutic approaches targeting LA. Our studies also suggest off target effects of MAZ51 on the vasculature in the setting of cisplatin nephrotoxicity.