Journal of the American Society of Nephrology : JASN · 2026
Vascular Endothelial Growth Factor Receptor 1-Blocking Antibody Improves Endothelial Structure, Kidney Function, and GFR in Diabetic Mice.
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Li Jingjun, Gonzalez Villalobos Romer A, Rutkoski Thomas J, Farrington Krista P, Chipashvili Vaja, Zheng Gang, Chen Tao, Yekkala Krishna, Locatelli Monica, Zoja Carlamaria, Benigni Ariela, Lutnick Brendon, Ho George, Reilly Dermot, Zheng Xirong, Zheng Songmao, Bialecki Russell, Hansen Michael K, Wu Haojia, Humphreys Benjamin D, Magnone Maria Chiara, Myshkin Eugene, Breyer Matthew D
Аннотация
KEY POINTS: We found evidence for reduced vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 activation in both human and mouse diabetic kidney disease. A monoclonal vascular endothelial growth factor receptor 1-blocking antibody improved urine albumin-creatinine ratio and GFR in a mouse model of accelerated diabetic kidney disease. The mechanism for this benefit appears to be linked to increased endogenous vascular endothelial growth factor A and differentiates from lisinopril.
BACKGROUND: Diabetic kidney disease (DKD) remains the major cause of kidney failure. Vascular endothelial growth factor A (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 vascular endothelial growth factor receptor 1 (VEGFR1; aka sflt1), the VEGFR1 ligands VEGFA, and placental growth factor were measured in human DKD plasma samples from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. We also tested the effects of monoclonal antibody designation for murinized anti-mouse VEGFR1 receptor (VGFB1), a murinized VEGFR1-blocking antibody in the uninephrectomy renin expressing adeno-associated virus db/db DKD mouse including translational end points 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 soluble Flt1 and placental growth factor were higher in CREDENCE participants with lower eGFR, while intrarenal VEGFA mRNA decreased with lower eGFR. VEGFR1 blockade with the VGFB1 mAb improved overall sinistrin clearance, serum creatinine, albuminuria, BP, and kidney structure in uninephrectomy renin expressing adeno-associated virus db/db mice. VGFB1 treatment benefit differentiated from lisinopril by increasing endothelial fenestrae and glycocalyx-related genes. Compared with 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.
BACKGROUND: Diabetic kidney disease (DKD) remains the major cause of kidney failure. Vascular endothelial growth factor A (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 vascular endothelial growth factor receptor 1 (VEGFR1; aka sflt1), the VEGFR1 ligands VEGFA, and placental growth factor were measured in human DKD plasma samples from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. We also tested the effects of monoclonal antibody designation for murinized anti-mouse VEGFR1 receptor (VGFB1), a murinized VEGFR1-blocking antibody in the uninephrectomy renin expressing adeno-associated virus db/db DKD mouse including translational end points 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 soluble Flt1 and placental growth factor were higher in CREDENCE participants with lower eGFR, while intrarenal VEGFA mRNA decreased with lower eGFR. VEGFR1 blockade with the VGFB1 mAb improved overall sinistrin clearance, serum creatinine, albuminuria, BP, and kidney structure in uninephrectomy renin expressing adeno-associated virus db/db mice. VGFB1 treatment benefit differentiated from lisinopril by increasing endothelial fenestrae and glycocalyx-related genes. Compared with 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.