Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury
Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury
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血管内皮生长因子受体 3 是改善甲基乙二醛诱导的腹膜损伤净超滤的新靶点
DOI：
10.1038/labinvest.2015.87
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发表时间：
2015
影响因子：
5
通讯作者：
Takei Y.
中科院分区：
文献类型：
--
作者：
Terabayashi T;Ito Y;Mizuno M;Suzuki Y;Kinashi H;Sakata F;Tomita T;Iguchi D;Tawada M;Nishio R;Maruyama S;Imai E;Matsuo S;Takei Y.
适当的液体平衡对于腹膜透析患者的良好临床结局和生存率非常重要。我们最近报道了通过转化生长因子-β1-血管内皮生长因子-C（VEGF-C）途径在腹腔内发生与纤维化相关的淋巴管生成。我们研究了VEGF受体3（VEGFR-3），VEGF-C和-D的受体，是否可能是一个新的目标，以改善净超滤，通过使用腺病毒表达可溶性VEGFR-3（Adeno-sVEGFR-3）在啮齿动物模型的腹膜损伤由甲基乙二醛（MGO）。我们证明了在这些MGO模型中，特别是在隔膜中，淋巴管生成发生，表明淋巴管生成是腹膜腔炎症和纤维化的共同特征。在MGO模型中，VEGF-D在膈肌中显著增加;然而，VEGF-C没有显著上调。在通过尾静脉注射给药后第50天检测到的Adeno-sVEGFR-3成功地抑制了小鼠MGO模型中隔膜和壁层腹膜中的淋巴管生成，而对纤维化、炎症或新血管生成没有显著影响。Adeno-sVEGFR-3在炎症减轻后第22天（P< 0.05）和第50天（P< 0.01）改善了使用7.5%艾考糊精腹膜透析液的腹膜平衡试验（7.5%艾考糊精腹膜平衡试验）中的引流量，表明7.5%艾考糊精腹膜平衡试验识别了淋巴管生成的变化。溶质转运率不受淋巴管生成抑制的影响。在人类腹膜透析患者中，透析液/血浆肌酐比值与透析液VEGF-D浓度呈正相关（P< 0.001）。VEGF-D mRNA在超滤失败患者的腹膜中显著升高，表明VEGF-D参与腹膜透析患者淋巴管生成的发展。这些结果表明，VEGFR-3是通过抑制淋巴吸收改善净超滤的新靶点，7.5%艾考糊精腹膜平衡试验可用于估计淋巴吸收。
Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-β1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and-D, might be a new target to improve net ultrafiltration by using adenovirus-expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (P< 0.05) and day 50 after reduction of inflammation (P< 0.01), indicating that the 7.5% icodextrin peritoneal equilibration test identifies changes in lymphangiogenesis. The solute transport rate was not affected by suppression of lymphangiogenesis. In human peritoneal dialysis patients, the dialysate to plasma ratio of creatinine positively correlated with the dialysate VEGF-D concentration (P< 0.001). VEGF-D mRNA was significantly higher in the peritoneal membranes of patients with ultrafiltration failure, indicating that VEGF-D is involved in the development of lymphangiogenesis in peritoneal dialysis patients. These results indicate that VEGFR-3 is a new target to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption.