The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System
The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System
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DOI：
10.1161/hypertensionaha.111.173559
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发表时间：
2011-08-01
期刊：
影响因子：
8.3
通讯作者：
van den Meiracker, Anton H.
中科院分区：
文献类型：
--
作者：
Kappers, Mariette H. W.;Smedts, Frank M. M.;van den Meiracker, Anton H.
血管生成抑制是几种肿瘤类型的既定治疗方法。不幸的是，这种疗法伴有不良反应，包括高血压和肾毒性，被称为“先兆子痫”。最近，我们在患者和大鼠中证实，多靶点酪氨酸激酶抑制剂舒尼替尼会导致血压（BP）升高、肾功能障碍以及与内皮素系统激活相关的蛋白尿。在当前的研究中，我们研究了舒尼替尼对大鼠肾脏组织学的影响，包括与先兆子痫的相似性，以及内皮素1、一氧化氮（NO）生物利用度降低和氧化应激增加在舒尼替尼诱导的高血压和肾毒性发展中的作用。在服用舒尼替尼的大鼠中，光镜和电镜检查显示明显的肾小球内皮病，这是先兆子痫的一个特征性组织学特征，在停用舒尼替尼后部分可逆。组织学异常伴有内皮素1尿排泄增加和NO代谢物排泄减少。在单独服用舒尼替尼的大鼠中，血压升高（ΔBP：31.6±0.9 mmHg）。这种升高在很大程度上可被内皮素受体拮抗剂马西替坦预防（ΔBP：12.3±1.5 mmHg），而被超氧化物歧化酶模拟物Tempol仅轻度预防（ΔBP：25.9±2.3 mmHg）。这两种化合物都不能预防舒尼替尼诱导的血清肌酐升高或肾脏组织学异常，对尿硝酸盐没有影响，但可降低蛋白尿和内皮素1尿排泄。我们的研究结果表明，内皮素系统和氧化应激在舒尼替尼诱导的蛋白尿发展中都起重要作用，并且内皮素系统而非氧化应激对舒尼替尼诱导的高血压发展很重要。（《高血压》2011年；58：295 - 302）
Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (Delta BP: 31.6 +/- 0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (Delta BP: 12.3 +/- 1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (Delta BP: 25.9 +/- 2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension. (Hypertension. 2011;58:295-302.)