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Treatment with the vascular disrupting agent Combretastatin is associated with impaired AQP2 trafficking and increased urine output

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Combretastatin A-4 disodium phosphate (CA4P) is a vascular disrupting agent known to mediate its effects primarily on tumor blood vessels. CA4P has previously been shown to induce a significant increase in mean arterial blood pressure and in haemoglobin concentration in mice. In the present study we examined whether this is associated with a general leakage of water into certain tissues or with changes in renal water handling. Munich-Wistar rats received either CA4P (30 mg/kg bodyweight) or saline i.p. as a bolus injection. One hour later haemoglobin concentration and mean blood pressure increased significantly. Magnetic resonance imaging (MRI) showed no significant changes in tissue water content following CA4P administration. However, urine output and salt excretion increased one hour after CA4P treatment, without changes in urinary and medullary osmolality. Aquaporin 2 (AQP2) mRNA levels in kidney inner medulla did not change one hour after CA4P treatment, but semiquantitative confocal laser scanning microscopy analysis demonstrated a decrease in phosphorylated AQP2 (pS256-AQP2) apical distribution within the collecting ducts of CA4P-treated rats compared to the characteristic apical localization in control rats. Furthermore, we demonstrated that CA4P caused disruption of microtubules and a weaker apical labelling of pS256-AQP2 in collecting duct principal cells within one hour. In conclusion, our data indicates that water escapes from the vascular system after CA4P treatment and it might take place primarily through a renal mechanism. The CA4P-mediated increased urine output seems to be a local effect in the collecting ducts due to reduced AQP2 trafficking to the apical plasma membrane.
Original languageEnglish
JournalAmerican Journal of Physiology: Regulatory, Integrative and Comparative Physiology
Pages (from-to)R186-R198
Number of pages13
Publication statusPublished - 2012

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