Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

Abstract

Abstract-Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency of these side effects. Normotensive Wistar Kyoto rats were exposed to 3 different doses of sunitinib or vehicle. After 8 days, rats were euthanized. Telemetrically measured blood pressure rose dose dependently, from 13 to 30 mm Hg. Proteinuria was present at all doses, but a rise in cystatin C occurred only at the intermediate and high doses. Compared with vehicle circulating endothelin-1 increased dose dependently, whereas 24-hour urinary endothelin excretion decreased. Light and electron microscopy revealed glomerular endotheliosis and ischemia with the intermediate and high doses of sunitinib but completely absent histological abnormalities with the low dose. Podocyte number per glomerular circumference did not change. Glomerular nephrin, Neph1, podocin, and endothelin-converting enzyme gene expression were downregulated in a dose-dependent manner.We conclude that the sunitinib-induced rise in blood pressure requires lower doses than its induction of renal function impairment and that functional changes in glomerular filtration barrier contribute to the occurrence of proteinuria, given the lack of histopathologic changes with the low dose of sunitinib. (Hypertension. 2015;66:543-549.

Vascular endothelial growth factor signaling is necessary for expansion of medullary microvessels during postnatal kidney development

“…B: CD31 immunostainings of cross sections of the renal outer medulla at P12. Representative pictured are shown at a magnification of ϫ10/ϫ40; scale bars ϭ 200/100 m. ficient VEGFR2 inhibition is likely since growth attenuation and proteinuria was observed as previously described (18,29,33). Whole body growth was impaired stronger than renal growth as judged from the increased kidney/body weight ratio and the lower protein/dsDNA ratio in kidney tissue.…”

Renal Soluble Guanylate Cyclase Is Downregulated in Sunitinib‐Induced Hypertension

“…It has recently been shown that renal cGMP excretion is reduced in rats with sunitinib‐induced hypertension,25, 26 which may be a consequence of low renal NO bioavailability 11, 16, 24. In keeping with this finding, the phosphodiesterase inhibitor sildenafil failed to attenuate the arterial pressure rise in sunitinib‐treated rats 26.…”

“…We focus on the early phase of developing sunitinib‐induced hypertension to investigate mechanisms that lead to the arterial pressure rise with minimum interference by factors that may be secondary to vascular and renal damage 11, 25. A recent study in patients with renal cell carcinoma34 showed that the sunitinib‐induced arterial pressure rise is not preceded by reduced acetylcholine or sodium nitroprusside–induced forearm vasodilation.…”

“…In sunitinib‐treated rats, not only renal NO X excretion but also renal cGMP excretion is reduced 25. Renal cGMP is formed by natriuretic peptide receptors and the sGC,39 the latter being part of the signaling pathways of VEGF receptors that are expressed in renal epithelia 4, 5, 6.…”

Mechanisms of Hypertension and Renal Injury During Vascular Endothelial Growth Factor Signaling Inhibition

“…Our group also observed a decrease in urinary excretion of NO metabolites or its effector molecule cGMP in rats exposed to sunitinib. 35,36 In contrast, using the Langendorff-isolated heart model, the vasodilator response to bradykinin and sodium nitroprusside were both diminished as was the vasoconstrictor response to angiotensin II. 37 These findings suggest a general BRAF indicates proto-oncogene; cFms, colony forming factor; c-KIT, receptor tyrosine kinase protein; c-MET, hepatocyte growth factor receptor; CSF1, colony stimulating factor; EGFR, epithelial growth factor receptor; FDA, Food and Drug Administration; FGF, fibroblast growth factor; Flt3, FMS-like tyrosine kinase 3; LEK, proto-oncogene; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; RET, proto-oncogene; RAF, protooncogene; VEGF, vascular endothelial growth factor; and VEGFR, VEGF receptor.…”