title: Effect of high salt diet on blood pressure and renal damage during vascular endothelial growth factor inhibition with sunitinib.
abstract: Antiangiogenic treatment with the multitargeted vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib associates with a blood pressure (BP) rise and glomerular renal injury. Recent evidence indicates that VEGF derived from tubular cells is required for maintenance of the peritubular vasculature. In the present study, we focussed on tubular and glomerular pathology induced by sunitinib and explored whether a high salt (HS) diet augments the BP rise and renal abnormalities.
  
  
  
  Normotensive Wistar Kyoto (WKY) rats were exposed to a normal salt (NS) or HS diet for 2 weeks and subsequently for 8 days to sunitinib or vehicle administration after which the rats were euthanized and kidneys excised. Mean arterial pressure (MAP) was telemetrically measured. Urine was sampled for proteinuria and endothelinuria, and blood for measurement of endothelin-1, creatinine and cystatin C.
  
  
  
  Compared with the NS diet, MAP rapidly rose by 27 ± 3 mmHg with the HS diet. On sunitinib, MAP rose further by 15 ± 1 with the NS and by 23 ± 4 mmHg with the HS diet (P < 0.05). The HS diet itself had no effect on proteinuria, endothelinuria or the plasma levels of endothelin-1, creatinine and cystatin C. Only with the HS diet, sunitinib administration massively increased proteinuria and endothelinuria and these two parameters were related (r = 0.50, P < 0.01). Likewise, renal glomerular pathology was enhanced during sunitinib with the HS diet, whereas tubulointerstitial injury or reduced peritubular capillary density did not occur.
  
  
  
  An HS diet induces a marked BP rise in WKY rats and exacerbates both the magnitude of the BP rise and glomerular injury induced by sunitinib.
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lankhorst
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.affiliation: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Clahsen-van Groningen
authors.affiliation: Department of Pathology, Reinier de Graaf Gasthuis, Delft, The Netherlands.
authors.forename: Frank M M
authors.initials: FM
authors.lastname: Smedts
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D007211:Indoles / Q000633:toxicity*; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D008297:Male; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D011921:Rats, Inbred WKY; D017673:Sodium Chloride, Dietary / Q000633:toxicity*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D017673:Sodium Chloride, Dietary; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib
keywords: angiogenesis inhibition; kidney; salt; sunitinib; vascular endothelial growth factor