2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2006020124v1 18/3/719    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schumacher, V. A. Articles by Royer-Pokora, B. Search for Related Content PubMed PubMed Citation Articles by Schumacher, V. A. Articles by Royer-Pokora, B.

Impaired Glomerular Maturation and Lack of VEGF165b in Denys-Drash Syndrome

Valérie Anne Schumacher^*, Stefanie Jeruschke^*, Frank Eitner, Jan Ulrich Becker, Gerald Pitschke^*, Yasemin Ince^*, Jeffrey H. Miner, Ivo Leuschner^||, Rainer Engers^¶, Anne Schulze Everding^**, Monika Bulla^** and Brigitte Royer-Pokora^*

^* Institute of Human Genetics and Anthropology and ^¶ Institute of Pathology, Heinrich-Heine-University of Duesseldorf, Duesseldorf, Germany; Division of Nephrology and Clinical Immunology, University of Aachen, Aachen, Germany; Institute of Pathology and Neuropathology, University Hospital Essen, Essen, Germany; Renal Division, Departments of Internal Medicine and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri; ^|| Institute of Pediatric Pathology, University of Kiel, Germany; and ^** Department of Pediatrics, University Children’s Hospital of Muenster, Muenster, Germany

Address correspondence to: Dr. Valérie A. Schumacher, Department of Medicine, Children’s Hospital, Boston, MA 02115. Phone: 211-811-2356; Fax: 211-811-2538; E-mail: valerie.schumacher{at}childrens.harvard.edu

Received for publication February 6, 2006. Accepted for publication December 20, 2006.

Individuals with Denys-Drash syndrome (DDS) develop diffuse mesangial sclerosis, ultimately leading to renal failure. The disease is caused by mutations that affect the zinc finger structure of the Wilms’ tumor protein (WT1), but the mechanisms whereby these mutations result in glomerulosclerosis remain largely obscure. How WT1 regulates genes is likely to be complex, because it has multiple splice forms, binds both DNA and RNA, and associates with spliceosomes. Herein is described that in DDS podocytes, the ratio of both WT1 +KTS isoforms C to D differs considerably from that of normal child and adult control podocytes and more closely resembles fetal profiles. Aside from the delay in podocyte maturation, DDS glomeruli show swollen endothelial cells, reminiscent of endotheliosis, together with incompletely fused capillary basement membranes; a dramatic decrease in collagen 4(IV) and laminin 2 chains; and the presence of immature or activated mesangial cells that express -smooth muscle actin. Because appropriate vascular endothelial growth factor A (VEGF-A) expression is known to be essential for the development and maintenance of glomerular architecture and function, this article addresses the question of whether VEGF-A expression is deregulated in DDS. The data presented here show that DDS podocytes express high levels of the proangiogenic isoform VEGF165, but completely lack the inhibitory isoform VEGF165b. The VEGF165/VEGF165b ratio in DDS resembles that of fetal S-shaped bodies, rather than that of normal child or adult control subjects. The alteration in VEGF-A expression presented here may provide a mechanistic insight into the pathogenesis of DDS.

This article has been cited by other articles:

				D. G. Nowak, J. Woolard, E. M. Amin, O. Konopatskaya, M. A. Saleem, A. J. Churchill, M. R. Ladomery, S. J. Harper, and D. O. Bates Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors J. Cell Sci., October 15, 2008; 121(20): 3487 - 3495. [Abstract] [Full Text] [PDF]

				A. A. Morrison, R. L. Viney, M. A. Saleem, and M. R. Ladomery New insights into the function of the Wilms tumor suppressor gene WT1 in podocytes Am J Physiol Renal Physiol, July 1, 2008; 295(1): F12 - F17. [Abstract] [Full Text] [PDF]

				S. E. Quaggin and J. A. Kreidberg Development of the renal glomerulus: good neighbors and good fences Development, February 15, 2008; 135(4): 609 - 620. [Abstract] [Full Text] [PDF]

				M. R. Vaughan and S. E. Quaggin How Do Mesangial and Endothelial Cells Form the Glomerular Tuft? J. Am. Soc. Nephrol., January 1, 2008; 19(1): 24 - 33. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673