Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA139

Poster Communications

Effects of tyrosine kinase inhibitor treatment on the renal transcriptome

J. Witte1, J. Golchert2, M. Mühlbauer1, R. Rettig1, O. Grisk1

1. Physiology, University of Greifswald, Karlsburg, Germany. 2. Functional Genomics, University of Greifswald, Greifswald, Germany.

Antiangiogenic tyrosine kinase inhibitors are used in tumor treatment and cause severe arterial hypertension. We have shown that rats treated with the angiogenesis inhibitor sunitinib develop arterial hypertension within four days which is associated with reduced renal fractional sodium excretion. Extensive hypothesis-driven studies excluded activation of distal convoluted tubule and collecting duct sodium reabsorption mechanisms as well as renal endothelial dysfunction as contributing factors. The present study was performed to identify further renal candidate mechanisms involved in sunitinib-induced hypertension. Ten-week-old rats were instrumented with radiotelemetric devices for arterial pressure recordings under ketamine/xylazine anesthesia (100/10 mg*kg-1, i.p.). After a seven-day recovery period, animals were treated with sunitinib [15 mg/(kg*d)] or vehicle. After four days of treatment, animals were anesthetized (pentobarbital, 60 mg/kg, i.p.). Kidneys were removed, dissected into cortex and medulla and mRNA expression profiles were obtained using Affymetrix microarray technology. Within four days, arterial pressure increased by 20 mmHg in sunitinib-treated rats. Using a p < 0.05 and a ratio of expression levels > 1.5 for analyses of the microarray data, we found that sunitinib treatment induced seven genes in the renal cortex and three genes in the renal medulla. Applying these cut-offs, the number of repressed genes was 24 in the cortex and 88 in the medulla. Pathway analyses revealed sunitinib-induced inductions of prostaglandin synthesis and B lymphocyte signaling pathways as well as repression of VEGF receptor signaling pathways. Within these pathways we identified and confirmed (qPCR) increased cortical cyclooxygenase 2 (COX2) and decreased cortical soluble guanylate cyclase (sGC) mRNA abundances. Renin mRNA abundance was suppressed in the cortex and medulla. The number of differentially expressed renal genes is relatively small in early sunitinib-induced hypertension. Two enzymes, namely COX2 and sGC, known to be important regulators of renal sodium disposition were identified as candidates that may contribute to increased renal sodium reabsorption during the development of angiogenesis inhibitor-induced hypertension.

Where applicable, experiments conform with Society ethical requirements