Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glornerulonephritis
Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glornerulonephritis
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DOI：
10.1038/sj.ki.5000439
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发表时间：
2006-06-01
影响因子：
19.6
通讯作者：
Kaneko, S.
中科院分区：
文献类型：
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作者：
Hara, A.;Wada, T.;Kaneko, S.
血管内皮生长因子（VEGF）是一种有效的血管生成因子，维持肾脏肾小球和小管周围毛细血管（PTC）网络。已知可溶性形式的VEGF受体-1（可溶性fms样酪氨酸激酶1 (sFIt-1)）通过在循环中结合VEGF来调节VEGF活性。我们推测VEGF可能对进行性肾小球肾炎（GN）大鼠肾小球滤过屏障和血管网络的维持有益。为了在体内阻断VEGF活性，在抗肾小球基底膜抗诱导GN诱导前3天和诱导后2周，分别用编码小鼠sFIt-1基因的质粒DNA转染大鼠股骨肌2次。sFIt-1抑制VEGF导致肾病大鼠大量尿蛋白排泄，同时下调肾素的表达。此外，阻断VEGF可诱导正常大鼠轻度蛋白尿。注射sfit1既不影响巨噬细胞的浸润，也不影响月牙体的形成。相反，sfit1治疗加速了肾小球硬化和间质纤维化的进展，并在第56天伴有肾功能障碍和PTC丢失。VEGF可能在维持足细胞功能和肾血管系统中发挥作用，从而保护肾小球和间质免受进行性肾损害。
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that maintains the glomerular and peritubular capillary (PTC) network in the kidney. The soluble form of the VEGF receptor-1 (soluble fms-like tyrosine kinase 1 (sFIt-1)) is known to regulate VEGF activity by binding VEGF in the circulation. We hypothesized that VEGF may be beneficial for maintaining glomerular filtration barrier and vascular network in rats with progressive glomerulonephritis (GN). For blockade of VEGF activity in vivo, rats were transfected twice with plasmid DNA encoding the murine sFIt-1 gene into femoral muscle 3 days before and 2 weeks after the induction of antiglomerular basement membrane anti body-induced GN. Inhibition of VEGF with sFIt-1 resulted in massive urinary protein excretion, concomitantly with downregulated expression of nephrin in nephritic rats. Further, blockade of VEGF induced mild proteinuria in normal rats. Administration of sFIt-1 affected neither the infiltration of macrophages nor crescentic formation. In contrast, treatment of sFIt-1 accelerated the progression of glomerulosclerosis and interstitial fibrosis accompanied with renal dysfunction and PTC loss at day 56. VEGF may play a role in maintaining the podocyte function as well as renal vasculature, thereby protecting glomeruli and interstitium from progressive renal insults.