Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival.
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.
Eremina
Vera
V
Department of Maternal & Fetal Health, The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 855Q, 600 University of Toronto, Ontario, Canada M5G 1X5.
Cui
Shiying
S
Gerber
Hanspeter
H
Ferrara
Napoleone
N
Haigh
Jody
J
Nagy
Andras
A
Ema
Masatsugu
M
Rossant
Janet
J
Jothy
Serge
S
Miner
Jeffrey H
JH
Quaggin
Susan E
SE
D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005920:Glomerular Mesangium / Q000166:cytology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism; D011336:Probability; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A