Stevens Megan, Oltean Sebastian
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, EX1 2LU, UK.
Genes (Basel). 2018 Feb 15;9(2):98. doi: 10.3390/genes9020098.
Vascular endothelial growth factor A (VEGF-A) is a prominent pro-angiogenic and pro-permeability factor in the kidney. Alternative splicing of the terminal exon of VEGF-A through the use of an alternative 3' splice site gives rise to a functionally different family of isoforms, termed VEGF-Ab, known to have anti-angiogenic and anti-permeability properties. Dysregulation of the VEGF-A/VEGF-Ab isoform balance has recently been reported in several kidney pathologies, including diabetic nephropathy (DN) and Denys-Drash syndrome. Using mouse models of kidney disease where the VEGF-A isoform balance is disrupted, several reports have shown that VEGF-Ab treatment/over-expression in the kidney is therapeutically beneficial. Furthermore, inhibition of certain splice factor kinases involved in the regulation of VEGF-A terminal exon splicing has provided some mechanistic insight into how VEGF-A splicing could be regulated in the kidney. This review highlights the importance of further investigation into the novel area of VEGF-A splicing in chronic kidney disease pathogenesis and how future studies may allow for the development of splicing-modifying therapeutic drugs.
血管内皮生长因子A（VEGF-A）是肾脏中一种重要的促血管生成和促通透性因子。VEGF-A末端外显子通过使用替代的3'剪接位点进行可变剪接，产生了一个功能不同的异构体家族，称为VEGF-Ab，已知其具有抗血管生成和抗通透性特性。最近在包括糖尿病肾病（DN）和迪尼-德拉斯综合征在内的几种肾脏疾病中报道了VEGF-A/VEGF-Ab异构体平衡的失调。使用VEGF-A异构体平衡被破坏的肾脏疾病小鼠模型，多项报告表明，在肾脏中进行VEGF-Ab治疗/过表达具有治疗益处。此外，抑制参与VEGF-A末端外显子剪接调控的某些剪接因子激酶，为肾脏中VEGF-A剪接的调控机制提供了一些见解。本综述强调了进一步研究VEGF-A剪接在慢性肾脏病发病机制这一新兴领域的重要性，以及未来研究如何可能促进剪接修饰治疗药物的开发。
