A mutant form of the Wilms' tumor suppressor gene WT1 observed in Denys-Drash syndrome interferes with glomerular capillary development.
The Wilms' tumor suppressor gene WT1 encodes a zinc finger protein that is required for urogenital development. In the kidney, WT1 is most highly expressed in glomerular epithelial cells or podocytes, which are an essential component of the filtering system. Human subjects heterozygous for point mutations in the WT1 gene develop renal failure because of the formation of scar tissue within glomeruli. The relationship between WT1 expression in podocytes during development and glomerular scarring is not well understood. In this study, transgenic mice that expressed a mutant form of WT1 in podocytes were derived. The capillaries within transgenic glomeruli were dilated, indicating that WT1 might regulate the expression of growth factors that affect capillary development. Platelet endothelial cell adhesion molecule-1 expression was greatly reduced on glomerular endothelial cells of transgenic kidneys. These results suggest that WT1 controls the expression of growth factors that regulate glomerular capillary development and that abnormal capillary development might lead to glomerular disease.
Natoli
Thomas A
TA
Department of Medicine and Laboratory for Skeletal Disorders and Rehabilitation, Department of Orthopedic Surgery, Children's Hospital, Boston, Massachusetts 02115, USA.
Liu
Jing
J
Eremina
Vera
V
Hodgens
Karen
K
Li
Cong
C
Hamano
Yuki
Y
Mundel
Peter
P
Kalluri
Raghu
R
Miner
Jeffrey H
JH
Quaggin
Susan E
SE
Kreidberg
Jordan A
JA
D000818:Animals; D002196:Capillaries / Q000254:growth & development / Q000473:pathology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D003598:Cytoskeletal Proteins / Q000378:metabolism; D030321:Denys-Drash Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004622:Embryo, Mammalian / Q000473:pathology; D015870:Gene Expression; D016162:Genes, Wilms Tumor; D016023:Integrins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic / Q000196:embryology / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics*
D003598:Cytoskeletal Proteins; D016023:Integrins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D025721:WT1 Proteins