Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival |
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Authors: | Eremina Vera Cui Shiying Gerber Hanspeter Ferrara Napoleone Haigh Jody Nagy Andras Ema Masatsugu Rossant Janet Jothy Serge Miner Jeffrey H Quaggin Susan E |
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Institution: | Department of Maternal & Fetal Health, The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 855Q, 600 University of Toronto, Ontario, Canada M5G 1X5. |
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Abstract: | The glomerular filtration barrier separates the blood from the urinary space and consists of two major cell types: podocytes and fenestrated endothelial cells. Mesangial cells sit between the capillary loops and provide structural support. Proliferation and loss of mesangial cells both are central findings in a number of renal diseases, including diabetic nephropathy and mesangiolysis, respectively. Using cell-specific gene targeting, it was shown previously that vascular endothelial growth factor A (VEGF-A) production by podocytes is required for glomerular endothelial cell migration, differentiation, and survival. For further investigation of the effect of gene dose and VEGF-A knockdown within the glomerulus, mice that carry one hypomorphic VEGF-A allele and one podocyte-specific null VEGF-A allele (VEGFhypo/loxP,Neph-Cre+/-) were generated; in these mice, the "allelic dose" of VEGF-A is intermediate between glomerular-specific heterozygous and null states. VEGFhypo/loxP,Neph-Cre+/- mice die at 3 wk of age from renal failure. Although endothelial cell defects are observed, striking loss of mesangial cells occurs postnatally. In addition, differentiated mesangial cells cannot be found in glomeruli of podocyte-specific null VEGF-A mice (VEGFloxP/loxP,Cre+/-). Together, these results demonstrate a key role for VEGF-A production in the podocyte for mesangial cell survival and differentiation. |
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