Rintala S E, Savikko J, Rintala J M, von Willebrand E
Transplantation LaboratoryUniversity of Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
Transplant Proc. 2006 Dec;38(10):3236-8. doi: 10.1016/j.transproceed.2006.10.049.
Acute rejection is the single most important risk factor for the subsequent development of chronic allograft nephropathy (CAN), which is still the primary reason for late allograft loss in kidney transplantation. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that has an important role in the development and maintenance of physiological endothelium. While its role has been characterized in the pathology of diabetic nephropathy and preeclampsia, its role in the development of acute and chronic allograft rejection remains unclear.
Kidney transplantations were performed from DA to WF rats and syngeneic control transplantations were performed between DA rats. Normal kidneys were used as controls to evaluate physiological VEGF and VEGFR-1 expression. Allografted rats were immunosuppressed with cyclosporine (CsA) (1.5 mg/kg/d subcutaneously); and no immunosuppression was given to syngeneic grafts. Grafts were harvested at 5 and 90 days after transplantation for histology and immunohistochemistry (VEGF, VEGFR-1).
In normal kidneys VEGF ligand and receptor expression was almost nonexistent. Only mild glomerular, arterial, and tubular VEGF expression was seen. In syngeneic grafts, no histological signs of acute or chronic rejection were seen, whereas characteristics of both acute and chronic rejection were seen in CsA-treated allografts. Altough VEGF expression was increased in syngenic grafts when compared to controls it still remained mild in both the early and the late posttransplant period. In CsA-treated allografts moderate VEGF expression was seen already 5 days after transplantation; the expression increased at 90 days after transplantation. The same pattern was also discovered for VEGFR-1 expression although the difference was not as remarkable after 5 days.
Our results demonstrated that VEGF ligand and receptor expression was increased in both acute and chronic rejection. Our data suggested that VEGF may have an important role in the pathology of chronic rejection. Based on our findings VEGF inhibition could be a potential intervention to prevent CAN in clinical kidney transplantation.
急性排斥反应是随后发生慢性移植肾肾病（CAN）的唯一最重要的危险因素，而CAN仍是肾移植后期移植肾丢失的主要原因。血管内皮生长因子（VEGF）是一种促血管生成因子，在生理性内皮的发育和维持中起重要作用。虽然其在糖尿病肾病和先兆子痫的病理过程中的作用已得到明确，但它在急性和慢性移植排斥反应发生过程中的作用仍不清楚。
将DA大鼠的肾脏移植到WF大鼠体内，并在DA大鼠之间进行同基因对照移植。使用正常肾脏作为对照，以评估生理性VEGF和VEGFR-1的表达。同种异体移植大鼠用环孢素（CsA）（1.5mg/kg/d皮下注射）进行免疫抑制；同基因移植则不给予免疫抑制。在移植后5天和90天采集移植物进行组织学和免疫组织化学检查（VEGF、VEGFR-1）。
在正常肾脏中，VEGF配体和受体的表达几乎不存在。仅可见轻度的肾小球、动脉和肾小管VEGF表达。在同基因移植物中，未见急性或慢性排斥反应的组织学迹象，而在CsA处理的同种异体移植物中可见急性和慢性排斥反应的特征。与对照相比，同基因移植物中的VEGF表达虽有所增加，但在移植后的早期和晚期仍保持轻度。在CsA处理的同种异体移植物中，移植后5天即可见中度VEGF表达；移植后90天表达增加。VEGFR-1表达也呈现相同模式，尽管5天后差异不明显。
我们的结果表明，VEGF配体和受体的表达在急性和慢性排斥反应中均增加。我们的数据表明，VEGF可能在慢性排斥反应的病理过程中起重要作用。基于我们的研究结果，VEGF抑制可能是临床肾移植中预防CAN的一种潜在干预措施。
