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

TY - JOUR

T1 - Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

AU - Lankhorst, Stephanie

AU - Baelde, Hans J

AU - Kappers, Mariëtte H W

AU - Smedts, Frank M M

AU - Hansen, Alastair

AU - Clahsen-van Groningen, Marian C

AU - Sleijfer, Stefan

AU - Mathijssen, Ron H J

AU - Danser, A H Jan

AU - van den Meiracker, Anton H

N1 - © 2015 American Heart Association, Inc.

PY - 2015/9/14

Y1 - 2015/9/14

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents

KW - Blood Pressure

KW - Dose-Response Relationship, Drug

KW - Indoles

KW - Kidney

KW - Kidney Diseases

KW - Male

KW - Podocytes

KW - Protein Kinase Inhibitors

KW - Pyrroles

KW - Rats

KW - Rats, Inbred WKY

KW - Vascular Endothelial Growth Factor A

U2 - 10.1161/hypertensionaha.115.05435

DO - 10.1161/hypertensionaha.115.05435

M3 - Journal article

C2 - 26195484

SN - 0194-911X

VL - 66

SP - 543

EP - 549

JO - Hypertension

JF - Hypertension

IS - 3

ER -