VEGFR1-Blocking Antibody Improves Endothelial Structure, Kidney Function, and GFR in Diabetic Mice

BACKGROUND: Diabetic kidney disease remains the major cause of kidney failure. VEGFA neutralizing antibodies also cause kidney disease in normal people. The present studies explored whether endogenous VEGFA deficiency might contribute to DKD. METHODS: Plasma soluble VEGFR1 (aka sflt1), and the VEGFR1 ligands VEGFA, and placental growth factor (PlGF), were measured human DKD plasma samples from the CREDENCE trial. We also tested effects of VGFB1, a murinized VEGFR1-blocking antibody in the uninephrectomy ReninAAVdb/db DKD mouse including translational endpoints of serum creatinine and overall survival. Histology, transmission electron microscopy and RNA sequencing of mouse kidneys treated with or without VGFB1 or lisinopril were compared. RESULTS: Circulating sFlt1 and PlGF, increased in CREDENCE while intrarenal VEGFA mRNA decreased as GFR declined. VEGFR1 blockade with the VGFB1 mAb improved overall sinistrin clearance, serum creatinine, albuminuria, blood pressure, and kidney structure in uninephrectomy ReninAAVdb/db mice. VGFB1 treatment benefit differentiated from lisinopril by increasing endothelial fenestrea and glycocalyx related genes. Compared to lisinopril, VGFB1 also significantly increased glomerular endothelial genes including Emcn, Esm1, Ehd3 and Exoc3l2. CONCLUSIONS: An anti-VEGFR1 antibody restored VEGFA activity, endothelial health, and GFR in severe murine DKD. This effect was via a mechanism distinct from lisinopril.