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Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus

Overview of attention for article published in PLOS ONE, July 2012
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Title
Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus
Published in
PLOS ONE, July 2012
DOI 10.1371/journal.pone.0040589
Pubmed ID
Authors

Delma Veron, Guillermo Villegas, Pardeep Kumar Aggarwal, Claudia Bertuccio, Juan Jimenez, Heino Velazquez, Kimberly Reidy, Dale R. Abrahamson, Gilbert Moeckel, Michael Kashgarian, Alda Tufro

Abstract

Podocyte or endothelial cell VEGF-A knockout causes thrombotic microangiopathy in adult mice. To study the mechanism involved in acute and local injury caused by low podocyte VEGF-A we developed an inducible, podocyte-specific VEGF-A knockdown mouse, and we generated an immortalized podocyte cell line (VEGF(KD)) that downregulates VEGF-A upon doxycycline exposure. Tet-O-siVEGF:podocin-rtTA mice express VEGF shRNA in podocytes in a doxycycline-regulated manner, decreasing VEGF-A mRNA and VEGF-A protein levels in isolated glomeruli to ~20% of non-induced controls and urine VEGF-A to ~30% of control values a week after doxycycline induction. Induced tet-O-siVEGF:podocin-rtTA mice developed acute renal failure and proteinuria, associated with mesangiolysis and microaneurisms. Glomerular ultrastructure revealed endothelial cell swelling, GBM lamination and podocyte effacement. VEGF knockdown decreased podocyte fibronectin and glomerular endothelial alpha(V)beta(3) integrin in vivo. VEGF receptor-2 (VEGFR2) interacts with beta(3) integrin and neuropilin-1 in the kidney in vivo and in VEGF(KD) podocytes. Podocyte VEGF knockdown disrupts alpha(V)beta(3) integrin activation in glomeruli, detected by WOW1-Fab. VEGF silencing in cultured VEGF(KD) podocytes downregulates fibronectin and disrupts alpha(V)beta(3) integrin activation cell-autonomously. Collectively, these studies indicate that podocyte VEGF-A regulates alpha(V)beta(3) integrin signaling in the glomerulus, and that podocyte VEGF knockdown disrupts alpha(V)beta(3) integrin activity via decreased VEGFR2 signaling, thereby damaging the three layers of the glomerular filtration barrier, causing proteinuria and acute renal failure.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 49 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Ireland 1 2%
Unknown 48 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 13 27%
Student > Master 6 12%
Researcher 5 10%
Student > Doctoral Student 5 10%
Other 4 8%
Other 9 18%
Unknown 7 14%
Readers by discipline Count As %
Medicine and Dentistry 15 31%
Agricultural and Biological Sciences 13 27%
Biochemistry, Genetics and Molecular Biology 6 12%
Pharmacology, Toxicology and Pharmaceutical Science 3 6%
Immunology and Microbiology 2 4%
Other 4 8%
Unknown 6 12%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 July 2012.
All research outputs
#20,161,674
of 22,671,366 outputs
Outputs from PLOS ONE
#172,677
of 193,517 outputs
Outputs of similar age
#148,262
of 164,702 outputs
Outputs of similar age from PLOS ONE
#3,678
of 4,011 outputs
Altmetric has tracked 22,671,366 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 193,517 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 15.0. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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