Effect of high salt diet on blood pressure and renal damage during vascular endothelial growth factor inhibition with sunitinib
Effect of high salt diet on blood pressure and renal damage during vascular endothelial growth factor inhibition with sunitinib
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DOI：
10.1093/ndt/gfv410
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发表时间：
2016-06-01
影响因子：
6.1
通讯作者：
van den Meiracker, Anton H.
中科院分区：
文献类型：
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作者：
Lankhorst, Stephanie;Baelde, Hans J.;van den Meiracker, Anton H.
背景多靶点血管内皮生长因子（VEGF）受体抑制剂舒尼替尼的抗血管生成治疗与血压（BP）升高和肾小球肾损伤相关。最近的证据表明，血管内皮生长因子来源于肾小管细胞所需的维持管周脉管系统。在本研究中，我们关注舒尼替尼引起的肾小管和肾小球病理学，并探讨高盐饮食是否会增加血压升高和肾脏异常。将血压正常的Wistar京都（WKY）大鼠暴露于正常盐（NS）或HS饮食2周，随后给予舒尼替尼或载体8天，之后将大鼠安乐死并切除肾脏。遥测平均动脉压（MAP）。取尿标本检测蛋白尿和内皮素尿，取血检测内皮素-1、肌酐和胱抑素C。与NS饮食相比，HS饮食的MAP迅速升高27 +/- 3 mmHg。舒尼替尼组，NS组MAP进一步升高15 +/- 1 mmHg，HS组MAP进一步升高23 +/- 4 mmHg（P < 0.05）。HS饮食本身对蛋白尿、内皮素尿或内皮素-1、肌酐和胱抑素C的血浆水平没有影响。仅在HS饮食下，舒尼替尼显著增加蛋白尿和内皮素尿，且两者相关（r = 0.50，P < 0.01）。同样地，在舒尼替尼与HS饮食的治疗过程中，肾小球病理学增强，而肾小管间质损伤或肾小管周围毛细血管密度降低并未发生。HS饮食诱导WKY大鼠血压显著升高，并加剧舒尼替尼诱导的血压升高幅度和肾小球损伤。
Background. 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.Methods. 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.Results. 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.Conclusions. 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.