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Molecular and Cellular Biology, September 2005, p. 7441-7448, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7441-7448.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Vascular Endothelial Growth Factor Induces Branching Morphogenesis/Tubulogenesis in Renal Epithelial Cells in a Neuropilin-Dependent Fashion

Anil Karihaloo,1* S. Ananth Karumanchi,2 William L. Cantley,1 Shivalingappa Venkatesha,1 Lloyd G. Cantley,1 and Sujata Kale1

Yale University School of Medicine, New Haven, Connecticut 06510,1 Department of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts2

Received 2 April 2005/ Returned for modification 26 May 2005/ Accepted 6 June 2005

Vascular endothelial growth factor (VEGF) is well characterized for its role in endothelial cell differentiation and vascular tube formation. Alternate splicing of the VEGF gene in mice results in various VEGF-A isoforms, including VEGF-121 and VEGF-165. VEGF-165 is the most abundant isoform in the kidney and has been implicated in glomerulogenesis. However, its role in the tubular epithelium is not known. We demonstrate that VEGF-165 but not VEGF-121 induces single-cell branching morphogenesis and multicellular tubulogenesis in mouse renal tubular epithelial cells and that these morphogenic effects require activation of the phosphatidylinositol 3-kinase (PI 3-K) and, to a lesser degree, the extracellular signal-regulated kinase and protein kinase C signaling pathways. Further, VEGF-165-stimulated sheet migration is dependent only on PI 3-K signaling. These morphogenic effects of VEGF-165 require activation of both VEGF receptor 2 (VEGFR-2) and neuropilin-1 (Nrp-1), since neutralizing antibodies to either of these receptors or the addition of semaphorin 3A (which blocks VEGF-165 binding to Nrp-1) prevents the morphogenic response and the phosphorylation of VEGFR-2 along with the downstream signaling. We thus conclude that in addition to endothelial vasculogenesis, VEGF can induce renal epithelial cell morphogenesis in a Nrp-1-dependent fashion.

* Corresponding author. Mailing address: Section of Nephrology, Yale University School of Medicine, New Haven, CT 06510. Phone: (203) 785-7111. Fax: (203) 785-4904. E-mail: Anil.Karihaloo{at}yale.edu.

Molecular and Cellular Biology, September 2005, p. 7441-7448, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7441-7448.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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