The Accumulation of VEGFA in the Glomerular Basement Membrane and Its Relationship with Podocyte Injury and Proteinuria in Alport Syndrome.

Haiyan Wang,Ting Liu,Jinlang Wu,Liangzhong Sun,Ying Mo,Zhihui Yue,Xiaoyun Jiang,Zhanjun Jia

doi:10.1371/journal.pone.0135648

Haiyan Wang, Ting Liu + Show 6 more

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https://doi.org/10.1371/journal.pone.0135648

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Journal: PloS one	Publication Date: Aug 14, 2015
Citations: 12	License type: CC BY 4.0

Affiliation: Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Abstract

The pathogenesis of proteinuria in Alport syndrome (AS) remains unclear. Vascular endothelial growth factor A (VEGFA) is a key regulator of the glomerular filtration barrier (GFB). This study explored the expression of VEGFA in the glomeruli and its accumulation in the glomerular basement membrane (GBM) and their relationship with podocyte injury and proteinuria in Alport syndrome (AS). Clinical data and renal tissues of control patients (11 cases) and AS patients (25 cases) were included. AS patients were further divided into 2 groups according to the quantities of their urinary protein: mild to moderate proteinuria group (proteinuria <50 mg/kg/d, 15 cases) and heavy proteinuria group (proteinuria ≥50 mg/kg/d, 10 cases). The expression and distribution of VEGFA and VEGF receptor 2 (VEGFR2) in the GFB, the phosphorylation of VEGFR2 (p-VEGFR2) and nephrin (p-nephrin), and the expression of synaptopodin and nephrin in the glomeruli were detected by immune electron microscopy and/or immunofluorescence, and their relationships to proteinuria in AS patients were analyzed. The accumulation of VEGFA in the GBM was increased in AS patients. The expression of VEGFA and the levels of p-VEGFR2 and p-nephrin in glomeruli were increased and were positively correlated with the degree of proteinuria in AS patients. The expression of synaptopodin and nephrin were decreased and were negatively correlated with the degree of proteinuria in AS patients. The over expressed VEGFA in the glomeruli and its accumulation in the GBM may activate the VEGFA-VEGFR2 and nephrin signaling pathways and lead to podocyte injury and occurrence of proteinuria in AS.

Highlights

Alport syndrome (AS) is the most common inherited progressive glomerulonephritis in children and it is caused by defects in type IV collagen (COL IV α3, α4 or α5 chain) in the glomerular basement membrane (GBM) [1, 2]
The present study explored the pathogenesis of proteinuria in AS by detecting the expression of Vascular endothelial growth factor A (VEGFA) and Vascular endothelial growth factor receptor 2 (VEGFR2) in glomeruli, the accumulation of VEGFA in GBM, the phosphorylation of VEGFR2 and nephrin, and the association of all of these markers with podocyte injury and the development of proteinuria in AS patients
We found that the level of p-nephrin was low in the control group and AS patients with mild proteinuria, but it was prominently increased in patients with heavy proteinuria and it was positively correlated with the degree of proteinuria

Summary

Introduction

Alport syndrome (AS) is the most common inherited progressive glomerulonephritis in children and it is caused by defects in type IV collagen (COL IV α3, α4 or α5 chain) in the glomerular basement membrane (GBM) [1, 2]. Vascular endothelial growth factor A (VEGFA) plays an important role in the maintenance of GFB function. Both the over-expression and the down-regulation of VEGFA could cause GFB injuries and the occurrence of proteinuria [4, 5]. Vascular endothelial growth factor receptor 2 (VEGFR2) is the main receptor for biological mediation function of VEGFA [6]. The present study explored the pathogenesis of proteinuria in AS by detecting the expression of VEGFA and VEGFR2 in glomeruli, the accumulation of VEGFA in GBM, the phosphorylation of VEGFR2 and nephrin, and the association of all of these markers with podocyte injury and the development of proteinuria in AS patients

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