Vascular Endothelial Growth Factor Down Regulates the Renal Epithelial Sodium Channel

Abstract

Vascular endothelial growth factor receptor (VEGFR) inhibitors, such as sunitinib, are widely used in tumor therapy. Their clinical use is limited by a rapidly developing arterial hypertension. We found that fractional sodium excretion was significantly reduced in sunitinib‐treated rats without alterations in fractional lithium excretion suggesting increased sodium reabsorption in the distal nephron and/or collecting ducts (CD). Therefore, we tested the hypotheses that sunitinib increases renal epithelial sodium channel (ENaC) expression and alters subcellular ENaC localization in the rat renal CD. Further, we tested if VEGF down regulates ENaC expression in murine cortical CD (M1) cells.Sunitinib [15 mg/(kg*d), n = 7, for 4 days] had no significant effects on renal ENaC subunit mRNA abundances but significantly increased α‐ENaC protein abundance by 57% in the renal medulla. Subcellular localization studies with confocal laser microscopy revealed that sunitinib increased the α‐ENaC subunit within the apical plasma membrane of the principal cells in cortical and medullary CD. The subcellular localization of the β‐ and γ‐ENaC subunits was similar in sunitinib‐treated and sham‐treated animals. In aldosterone‐treated M1 cells, VEGF significantly reduced α‐, β‐ and γ‐ENaC mRNA abundances by 30%, 55% and 40%, respectively. Sunitinib diminished (α‐ and γ‐subunits) or prevented (β‐subunit) these effects. In addition, VEGF significantly decreased α‐ and β‐ENaC protein abundances in M1 cells and sunitinib antagonized these effects.We conclude that VEGF down regulates renal ENaC and that increased ENaC activity may contribute to the pathogenesis of VEGFR inhibitor‐induced arterial hypertension.