A Mutant Form of the Wilms’ Tumor Suppressor Gene WT1 Observed in Denys-Drash Syndrome Interferes with Glomerular Capillary Development THOMAS A. NATOLI,* † JING LIU,* † VERA EREMINA, ‡ KAREN HODGENS, § CONG LI,  YUKI HAMANO, †¶ PETER MUNDEL, # RAGHU KALLURI, ¶ JEFFREY H. MINER,  SUSAN E. QUAGGIN, ‡ ** and JORDAN A. KREIDBERG* † *Department of Medicine and § Laboratory for Skeletal Disorders and Rehabilitation, Department of Orthopedic Surgery, Children’s Hospital, Boston, Massachusetts; † Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; ‡ 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. 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 glo- meruli 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 expres- sion of growth factors that regulate glomerular capillary de- velopment and that abnormal capillary development might lead to glomerular disease. In nephrons of vertebrate kidneys, blood is filtered within the glomerulus, which is a structure that develops at the proximal end of each nephron during kidney development. Within the glomerulus, cells known as podocytes extend a fine meshwork of foot processes, forming scaffolding around a plexus of six to eight capillary loops (Figure 1). Situated between the podocyte foot processes and the endothelial lining of the capillaries is the glomerular basement membrane (GBM), which is an epithelial basement membrane whose presence prevents the exit of large macromolecules from the circulation. The maintenance of this glomerular structure is essential for survival. Improper devel- opment of the glomeruli, as occurs in several human syn- dromes, or subsequent damage from disease processes results in the loss of protein from the circulation, leading to a disease state known as the nephrotic syndrome and ultimately to chronic renal failure, necessitating dialysis or kidney transplantation. Studies of gene-targeted mice and human subjects with inherited kidney disease have defined two essential structural features of glomeruli that are necessary for maintenance of the structure of podocytes and the GBM (Figure 1). The first is the interaction of the laminin receptor 31 integrin with the GBM (1). Mutation of either the 3 integrin gene or compo- nents of the GBM leads to an inability to form or maintain the foot process structure or an intact GBM. The second, equally important structure is the slit diaphragm, which is a protein matrix situated between the lateral aspects of each pair of adjacent foot processes. Nephrin, the product of the gene mutated in the Finnish type of congenital nephrotic syndrome (2), was identified as a component of the slit diaphragm (3–5), and podocin, the product of the NPHS2 gene (which is mutated in steroid-resistant nephrotic syndrome) (6), is a membrane protein associated with the slit diaphragm and CD2-associated protein (CD2-AP) (7–9). The Wilms’ tumor-1 (WT1) gene encodes a protein, WT1, with a proline-rich amino-terminal domain and four carboxy- terminal zinc fingers, which is expressed throughout urogenital development and continues to be highly expressed in podo- Received March 21, 2002. Accepted April 29, 2002. Correspondence to Dr. Jordan A. Kreidberg, Division of Nephrology, Depart- ment 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@tch.harvard.edu 1046-6673/1308-2058 Journal of the American Society of Nephrology Copyright © 2002 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000022420.48110.4B J Am Soc Nephrol 13: 2058–2067, 2002