Vascular endothelial growth factor A signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival

被引:190
作者
Eremina, Vera
Cui, Shiying
Gerber, Hanspeter
Ferrara, Napoleone
Haigh, Jody
Nagy, Andras
Ema, Masatsugu
Rossant, Janet
Jothy, Serge
Miner, Jeffrey H.
Quaggin, Susan E.
机构
[1] Univ Toronto, Samuel Lunenfeld Res Inst, Mt Sinai Hosp, Dept Maternal & Fetal Hlth, Toronto, ON M5G 1X5, Canada
[2] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA
[3] Univ Ghent VIB, Dept Mol Biomed Res, Vasc Cell Biol Unit, B-9000 Ghent, Belgium
[4] Univ Toronto, St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada
[5] Univ Toronto, St Michaels Hosp, Div Nephrol, Toronto, ON M5B 1W8, Canada
[6] Washington Univ, Sch Med, Div Renal, Dept Internal Med, St Louis, MO 63110 USA
[7] Univ Tsukuba, Inst Basic Med Sci, Dept Anat & Embryol, Tsukuba, Ibaraki 305, Japan
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2006年 / 17卷 / 03期
关键词
D O I
10.1681/ASN.2005080810
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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 (VEGF(hypo/loxP), Neph-Cre(+/-)) were generated; in these mice, the "allelic dose" of VEGF-A is intermediate between glomerular-specific heterozygous and null states. VEGF(hypo/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 (VEGF(loxP/loxP), Cre(+/-)). Together, these results demonstrate a key role for VEGF-A production in the podocyte for mesangial cell survival and differentiation.
引用
收藏
页码:724 / 735
页数:12
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