Abstract
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-Axxxb, known to have anti-angiogenic and anti-permeability properties. Dysregulation of the VEGF-Axxx/VEGF-Axxxb 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-A165b 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.
Highlights
The human genome is comprised of approximately 20,000 genes, but the human proteome is estimated to be formed of hundreds of thousands of proteins [1]
This review highlights the importance of further investigation into the novel area of vascular endothelial growth factor A (VEGF-A) splicing in chronic kidney disease pathogenesis and how future studies may allow for the development of splicing-modifying therapeutic drugs
alternative splicing (AS) of VEGF-A can occur through the inclusion/exclusion of various exons, giving rise to a family of pro-angiogenic isoforms generically known as VEGF-Axxx (VEGF-A121, VEGF-A145, VEGF-A165, VEGF-A189, and VEGF-A206 —the number denotes the number of amino acids) [19]
Summary
The human genome is comprised of approximately 20,000 genes, but the human proteome is estimated to be formed of hundreds of thousands of proteins [1] This diversity is mainly the result of a process known as alternative splicing (AS); a single gene transcript can give rise to multiple proteins depending on the way the gene is spliced [2]. Alternative splicing of exon 8 of the VEGF-A gene results in the expression of an anti-angiogenic, anti-permeability, and cyto-protective family of isoforms, termed the VEGF-Axxx b family (the most common isoform being VEGF-A165 b) [13], which has been shown to be protective in kidney disease [9,10]. This review discusses the mechanism of VEGF-A splicing, highlights the importance of a balance of the VEGF-A exon 8 splice variants in the kidney, and examines the ways in which VEGF-A splicing can be manipulated to obtain therapeutic benefit
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