Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.
Kidney disease affects over 20 million people in the United States alone. Although the causes of renal failure are diverse, the glomerular filtration barrier is often the target of injury. Dysregulation of VEGF expression within the glomerulus has been demonstrated in a wide range of primary and acquired renal diseases, although the significance of these changes is unknown. In the glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion of the barrier between the blood and urinary spaces. In this paper, we show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli resulted in perinatal lethality. Mutant kidneys failed to develop a filtration barrier due to defects in endothelial cell migration, differentiation, and survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease.
Eremina
Vera
V
The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Sood
Manish
M
Haigh
Jody
J
Nagy
András
A
Lajoie
Ginette
G
Ferrara
Napoleone
N
Gerber
Hans-Peter
HP
Kikkawa
Yamato
Y
Miner
Jeffrey H
JH
Quaggin
Susan E
SE
D043925:Angiogenesis Inducing Agents / Q000235:genetics / Q000502:physiology*; D000818:Animals; D005786:Gene Expression Regulation; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000151:congenital / Q000209:etiology*; D007676:Kidney Failure, Chronic / Q000209:etiology; D007678:Kidney Glomerulus / Q000378:metabolism*; D051379:Mice; D009404:Nephrotic Syndrome / Q000209:etiology; D042461:Vascular Endothelial Growth Factor A
D043925:Angiogenesis Inducing Agents; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse