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Podocyte-Derived BMP7 Is Critical for Nephron Development

Itsuro Kazama^*, Zhen Mahoney, Jeffrey H. Miner, Daniel Graf, Aris N. Economides and Jordan A. Kreidberg^*

^* Division of Nephrology, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, and Harvard Stem Cell Institute, Cambridge, Massachusetts; Renal Division, Washington University School of Medicine, St. Louis, Missouri; Institute of Immunology, Biomedical Science Research Center, Vari, Greece; and Regeneron Pharmaceuticals, Tarrytown, New York

Correspondence: Dr. Jordan A. Kreidberg, Division of Nephrology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. Phone: 617-919-2951; Fax: 617-730-0129; E-mail: jordan.kreidberg{at}childrens.harvard.edu

Received for publication November 16, 2007. Accepted for publication July 23, 2008.

Individuals with congenital renal hypoplasia display a defect in the growth of nephrons during development. Many genes that affect the initial induction of nephrons have been identified, but little is known about the regulation of postinductive stages of kidney development. In the absence of the growth factor bone morphogenic protein 7 (BMP7), kidney development arrests after induction of a small number of nephrons. The role of BMP7 after induction, however, has not been fully investigated. Here, we generated a podocyte-specific conditional knockout of BMP7 (Bmp7^flox/flox;Nphs2-Cre⁺ [BMP7 CKO]) to study the role of podocyte-derived BMP7 in nephron maturation. By postnatal day 4, 65% of BMP7 CKO mice had hypoplastic kidneys, but glomeruli demonstrated normal patterns of laminin and collagen IV subunit expression. Developing proximal tubules, however, were reduced in number and demonstrated impaired cellular proliferation. We examined signaling pathways downstream of BMP7; the level of cortical phosphorylated Smad1, 5, and 8 was unchanged in BMP CKO kidneys, but phosphorylated p38 mitogen-activated protein kinase was significantly decreased. In addition, β-catenin was reduced in BMP7 CKO kidneys, and its localization to intracellular vesicles suggested that it had been targeted for degradation. In summary, these results define a BMP7-mediated regulatory axis between glomeruli and proximal tubules during kidney development.

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