Reversal of advanced diabetic kidney disease in mice treated with a monoclonal anti-VEGFR1 antibody.

INTRODUCTION: Diabetic kidney disease (DKD) continues to be the major cause of kidney failure, and its treatment is of key importance. Targeting VEGF-A has yielded conflicting results in DKD models. Here, we investigated the potential benefit of targeting VEGF-A or its receptors for the treatment of advanced mouse DKD.

METHODS: Our studies tested the effects of neutralizing antibodies targeting VEGF-A, VEGFR2, and VEGFR1 on kidney function and histopathology, in 4 different mouse models of DKD and chronic kidney disease (CKD).

RESULTS: Unlike previous reports, blocking VEGF-A using an anti-VEGF-A monoclonal antibody worsened albuminuria and kidney injury in uninephrectomized (unix) diabetic db/db mice. Similar results were seen with the anti-VEGFR2 antibody (DC101). In contrast, antibody MF1, a VEGFR1 selective monoclonal blocking antibody, dramatically decreased albuminuria, improved kidney function, and reduced renal histological injury in the remnant kidney mice, unix db/db mice with or without renin-AAV injection, and eNOS-/-db/db hypertensive mice. MF1 also improved animal survival. MF1 benefit persisted in albuminuric transgenic mice lacking the VEGFR1 cytoplasmic tyrosine kinase domain. In renin-AAV unix db/db mice with advanced DKD, we observed improved survival, reduced serum creatinine, and regression of established kidney histological changes following delayed MF1 treatment. VEGFR1 antibody increased circulating placental growth factor and VEGF-A as well as phosphorylation of kidney VEGFR2. MF1 reduced blood pressure in diabetic eNOS-/- mice and acutely increased the glomerular filtration rate in db/db mice.

CONCLUSIONS: Our studies demonstrate that blocking VEGFR1 improved kidney function and microvascular structure in models of progressive CKD. VEGFR1 blockade provided a promising novel therapeutic approach to reverse DKD progression.