Abstract
Key points Progressive depletion of all vascular endothelial growth factor A (VEGF‐A) splice isoforms from the kidney results in proteinuria and increased glomerular water permeability, which are both rescued by over‐expression of VEGF‐A165b only.VEGF‐A165b rescues the increase in glomerular basement membrane and podocyte slit width, as well as the decrease in sub‐podocyte space coverage, produced by VEGF‐A depletion.VEGF‐A165b restores the expression of platelet endothelial cell adhesion molecule in glomerular endothelial cells and glomerular capillary circumference.VEGF‐A165b has opposite effects to VEGF‐A165 on the expression of genes involved in endothelial cell migration and proliferation. Chronic kidney disease is strongly associated with a decrease in the expression of vascular endothelial growth factor A (VEGF‐A). However, little is known about the contribution of VEGF‐A splice isoforms to kidney physiology and pathology. Previous studies suggest that the splice isoform VEGF‐A165b (resulting from alternative usage of a 3′ splice site in the terminal exon) is protective for kidney function. In the present study, we show, in a quad‐transgenic model, that over‐expression of VEGF‐A165b alone is sufficient to rescue the increase in proteinuria, as well as glomerular water permeability, in the context of progressive depletion of all VEGF‐A isoforms from the podocytes. Ultrastructural studies show that the glomerular basement membrane is thickened, podocyte slit width is increased and sub‐podocyte space coverage is reduced when VEGF‐A is depleted, all of which are rescued in VEGF‐A165b over‐expressors. VEGF‐A165b restores the expression of platelet endothelial cell adhesion molecule‐1 in glomerular endothelial cells and glomerular capillary circumference. Mechanistically, it increases VEGF receptor 2 expression both in vivo and in vitro and down‐regulates genes involved in migration and proliferation of endothelial cells, otherwise up‐regulated by the canonical isoform VEGF‐A165. The results of the present study indicate that manipulation of VEGF‐A splice isoforms could be a novel therapeutic avenue in chronic glomerular disease.
Highlights
Chronic kidney disease (CKD) is a major health problem worldwide
Given the pathologies associated with vascular endothelial growth factor A (VEGF-A) inhibition and the strong association of decreased glomerular filtration rate (GFR) with low VEGF-A expression, we have addressed the hypothesis that a simplified injury model of progressive cell-specific inducible depletion of VEGF-A from the kidney can be rescued by over-expressing only the VEGF-A165b isoform
Albuminuria resulting from progressive depletion of VEGF-A in kidneys of inducible transgenic KO mice is rescued by constitutive expression of the human VEGF-A165b splice isoform
Summary
Chronic kidney disease (CKD) is a major health problem worldwide. In the USA, it is estimated that ß13% of the general population has CKD stages 1–4 (Snyder et al 2009) and, in Europe, the prevalence is higher at 16% (Meguid El Nahas & Bello, 2005). The renal replacement population inevitably consumes a disproportionate amount of health resources and is associated with a poor prognosis, with a 5 year survival rate of close to 50% for dialysis patients (https://www.renalreg.org/data/). In large part, this is contributed to by the association of proteinuria and CKD with increased risk of cardiovascular disease and mortality (Go et al 2004; Allison, 2010; Matsushita et al 2010). There is a clear physiological role of VEGF-A in the kidney, which is affected in various pathologies This suggests that restoring the function of VEGF-A could be therapeutically useful
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