Vascular Endothelial Growth Factor (VEGF) Inhibitors Induce Hypertension, Afferent Arteriolar Dysfunction, and Glomerular Injury

Abstract

VEGF plays a role in signaling and regulating tumor progression and metastasis via angiogenesis. Inhibition of angiogenesis by targeting VEGF signaling has proven to be a successful anticancer strategy for solid tumors. Unfortunately, hypertension and renal toxicity are common side effects of anti‐VEGF therapy. Moreover, the mechanisms by which VEGF inhibitors (VEGFi) exert these unwanted effects are not fully understood. The aim of this study is to investigate blood pressure regulation, vascular function and glomerular injury in animals treated with VEGFi. Rats were fed a high salt diet and treated with the VEGFi, Sorafenib or Sunitinib (20mg/kg/d) for 4 weeks. Rats were implanted with telemetry transmitters to measure blood pressure. At the end of the 4‐week period the afferent arteriolar response to ATP was measured and the second kidney processed for histology. Blood pressure was increased by 4 weeks of Sorafenib (151 □} 3 mmHg) or Sunitinib (129 □} 7 mmHg) compared to controls (107 □} 11 mmHg). Afferent arteriolar responses to ATP were attenuated by >50% in the VEGFi treated groups. Urinary albumin excretion, an indicator of renal injury, increased in the VEGFi treated groups. VEGFi treated rats also demonstrated a 3‐fold increase in the glomerular injury score.These results demonstrate that VEGFi, Sorafenib and Suninitb, increase blood pressure, as well as, cause vascular dysfunction and glomerular injury.