Angiogenesis inhibition is an established treatment for several tumor types. 
Unfortunately, this therapy is associated with adverse effects, including 
hypertension and renal toxicity, referred to as "preeclampsia." Recently, we 
demonstrated in patients and in rats that the multitarget tyrosine kinase 
inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, 
and proteinuria associated with activation of the endothelin system. In the 
current study we investigated the effects of sunitinib on rat renal histology, 
including the resemblance with preeclampsia, as well as the roles of endothelin 
1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress 
in the development of sunitinib-induced hypertension and renal toxicity. In rats 
on sunitinib, light and electron microscopic examination revealed marked 
glomerular endotheliosis, a characteristic histological feature of preeclampsia, 
which was partly reversible after sunitinib discontinuation. The histological 
abnormalities were accompanied by an increase in urinary excretion of endothelin 
1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP 
increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the 
endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly 
with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both 
compounds could not prevent the sunitinib-induced rise in serum creatinine or 
renal histological abnormalities and had no effect on urine nitrates but 
decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate 
that both the endothelin system and oxidative stress play important roles in the 
development of sunitinib-induced proteinuria and that the endothelin system 
rather than oxidative stress is important for the development of 
sunitinib-induced hypertension.