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J Am Soc Nephrol 13:2058-2067, 2002
© 2002 American Society of Nephrology

A Mutant Form of the Wilms’ Tumor Suppressor Gene WT1 Observed in Denys-Drash Syndrome Interferes with Glomerular Capillary Development

Thomas A. Natoli*,{dagger}, Jing Liu*,{dagger}, Vera Eremina{ddagger}, Karen Hodgens§, Cong Li||, Yuki Hamano{dagger},¶, Peter Mundel#, Raghu Kalluri, Jeffrey H. Miner||, Susan E. Quaggin{ddagger},** and Jordan A. Kreidberg*,{dagger}

*Department of Medicine and §Laboratory for Skeletal Disorders and Rehabilitation, Department of Orthopedic Surgery, Children’s Hospital, Boston, Massachusetts; {dagger}Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; {ddagger}Department of Maternal and Fetal Health, The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; ||Renal Division, Washington University School of Medicine, St. Louis, Missouri; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; #Departments of Medicine and Cell Biology, Albert Einstein College of Medicine, Bronx, New York; and **Division of Nephrology, St. Michael’s Hospital, Toronto, Ontario, Canada.

Correspondence to Dr. Jordan A. Kreidberg, Division of Nephrology, Department of Medicine, Hunnewell 3, Children’s Hospital, 300 Longwood Ave., Boston, MA 02115. Phone: 617-247-5194; Fax: 617-232-4315; E-mail: Jordan.Kreidberg{at}tch.harvard.edu

ABSTRACT. 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.




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