Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries
Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries
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DOI：
10.1016/j.amjhyper.2005.09.022
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发表时间：
2006-07-01
影响因子：
3.2
通讯作者：
Makino, Hirofumi
中科院分区：
文献类型：
--
作者：
Kitayama, Hiroyuki;Maeshima, Yohei;Makino, Hirofumi
背景：在多种血管生成因子中，血管内皮生长因子（VEGF）、血管生成素-1 （Ang1）和血管生成素-2 （Ang2）在调节血管生成和血管完整性中起着至关重要的作用。血管紧张素-II （ang II）输注引起高血压和局灶性肾小管间质损伤。在本研究中，我们在大鼠II输注模型中研究了与肾小管间质病变相关的VEGF、Ang1、Ang2及其相应受体的表达。方法：雄性Sprague-Dawley （SD）大鼠通过渗透微型泵输注angii或去甲肾上腺素（NE） 14 d。血管紧张素II 1型（AT,）或2型（AT(2)）受体拮抗剂（分别为氯沙坦或PD123319）或肼嗪。结果：氯沙坦组和pd123319组间质纤维化、单核/巨噬细胞浸润、小管周围毛细血管稀薄均明显减轻。VEGF和Ang1在皮质小管中的免疫反应性在angii的作用下升高，在氯沙坦或PD123319的作用下减弱。免疫印迹检测，氯沙坦可抑制ang II诱导的VEGF升高，PD123319可抑制ang II诱导的Ang1升高。PD123319可显著抑制ang II诱导的flk-1、flt-1 （VEGF受体）和tie-2 （Ang1受体）的升高。这些改变在肼嗪加angii或ne输注的动物中没有观察到。结论：上述结果表明，注入angii主要通过AT受体诱导VEGF表达，并主要通过AT2受体增加VEGF受体、tie-2的表达和Ang1/Ang2比值。VEGF/flk-1/flt-1的升高可能与血管通透性、单核细胞/巨噬细胞浸润、小管周围毛细血管疏松有关，Ang1/Ang2比值的升高可能是一种代偿机制，抵消了angii输注后VEGF诱导通透的作用。Am J Hypertens 2006；[19] [718-727] (c) 2006中华高血压杂志。
Background: Among various angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) play crucial roles in regulating angiogenesis and vascular integrity. Infusion of angiotensin-II (ang II) induces hypertension and focal renal tubulointerstitial injuries. In the present study we investigated the renal expression of VEGF, Ang1, Ang2, and corresponding receptors in association with tubulointerstitial lesions in a rat ang II infusion model.Methods: Male Sprague-Dawley (SD) rats received an infusion of ang II or norepinephrine (NE) through osmotic minipumps for 14 days. Angiotensin II type 1 (AT,) or type 2 (AT(2)) receptor antagonist (losartan or PD123319, respectively) or hydralazine was co-administered.Results: Interstitial fibrosis, infiltration of monocyte/macrophage, and peritubular capillary rarefaction induced by ang II was significantly attenuated in the losartan- or PD123319-treated groups. Immunoreactivity of VEGF and Ang1 in cortical tubules was increased by ang II and was attenuated by losartan or PD123319. The increase of VEGF induced by ang II was suppressed by losartan, and the increase of Ang1 induced by ang II was inhibited by PD123319 as detected by immunoblot. The increase of flk-1 and flt-1 (VEGF receptors) and tie-2 (Ang1 receptor) induced by ang II was significantly suppressed by PD123319. These alterations were not observed in hydralazine plus ang II or NE-infused animals.Conclusions: These results demonstrate that an infusion of ang II induced the expression of VEGF mainly through AT, receptors, and increased the expression of VEGF receptors, tie-2, and Ang1/Ang2 ratio mainly through AT2 receptors. The increase of VEGF/flk-1/flt-1 may be associated with vascular permeability, monocyte/macrophage infiltration, and rarefaction of peritubular capillaries, and the increase of the Ang1/Ang2 ratio may be a compensatory mechanism counteracting the permeability inducing effect of VEGF after ang II infusion. Am J Hypertens 2006;19:718-727 (c) 2006 American Journal of Hypertension, Ltd.