Among the genes strongly induced by hypoxia-induced transcription factors (HIFs) and highly expressed during kidney microvascular development is VEGF, which encodes a potent endothelial mitogen and chemoattractant critical for embryonic vasculogenesis and angiogenesis. In developing kidney, glomerular podocytes are particularly rich sources of VEGF, which probably serves to attract endothelial precursors into vascular clefts of immature glomeruli, promote their mitosis and differentiation into glomerular endothelial cells, and assist with maintenance of their highly differentiated state through maturation. Moreover, we have recently localized expression of HIF mRNA transcripts and protein to developing podocytes of immature glomeruli. This leads to our central hypothesis: HIF stabilization coordinates synthesis of VEGF and its receptors, and governs kidney microvascular development. To address this hypothesis, we have designed three complementary specific aims. First, we will determine whether HIFs are differentially stabilized in podocyte and endothelial cell lines exposed to different oxygen tensions. Additionally, we will selectively knockdown separate HIF alpha subunits, HIF-1 beta, and HIF gene target mRNAs, using small interfering RNA (siRNA) technologies in vitro. Second, we will determine whether kidney vascular development is affected in hybrid nephrons containing ES cells with crippled HIF activation and VEGF signaling systems. Third, we will examine in vivo consequences of losses and gains of HIF alpha subunits, using Cre-lox technology, among other approaches. These results should provide fundamentally new information on mechanisms governing renal microvessel development and maintenance, which may have broad applicability to blood vessel formation in general.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Wilder, Elizabeth L
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University of Kansas
Anatomy/Cell Biology
Schools of Medicine
Kansas City
United States
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Steenhard, Brooke M; Isom, Kathryn; Stroganova, Larysa et al. (2010) Deletion of von Hippel-Lindau in glomerular podocytes results in glomerular basement membrane thickening, ectopic subepithelial deposition of collagen {alpha}1{alpha}2{alpha}1(IV), expression of neuroglobin, and proteinuria. Am J Pathol 177:84-96
Abrahamson, Dale R (2009) Development of kidney glomerular endothelial cells and their role in basement membrane assembly. Organogenesis 5:275-87
Abrahamson, Dale R; Hudson, Billy G; Stroganova, Larysa et al. (2009) Cellular origins of type IV collagen networks in developing glomeruli. J Am Soc Nephrol 20:1471-9
Abrahamson, Dale R; Isom, Kathryn; Roach, Eileen et al. (2007) Laminin compensation in collagen alpha3(IV) knockout (Alport) glomeruli contributes to permeability defects. J Am Soc Nephrol 18:2465-72
Abrahamson, Dale R; St John, Patricia L; Isom, Kathryn et al. (2007) Partial rescue of glomerular laminin alpha5 mutations by wild-type endothelia produce hybrid glomeruli. J Am Soc Nephrol 18:2285-93
Steenhard, Brooke M; Freeburg, Paul B; Isom, Kathryn et al. (2007) Kidney development and gene expression in the HIF2alpha knockout mouse. Dev Dyn 236:1115-25
St John, Patricia L; Abrahamson, Dale R (2007) LacZ transgenic mice and immunoelectron microscopy: an ultrastructural method for dual localization of beta-galactosidase and horseradish peroxidase. J Histochem Cytochem 55:1207-11
Magenheimer, Brenda S; St John, Patricia L; Isom, Kathryn S et al. (2006) Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na(+),K(+),2Cl(-) Co-transporter-dependent cystic dilation. J Am Soc Nephrol 17:3424-37
Takahashi, Takamune; Takahashi, Keiko; Mernaugh, Raymond L et al. (2006) A monoclonal antibody against CD148, a receptor-like tyrosine phosphatase, inhibits endothelial-cell growth and angiogenesis. Blood 108:1234-42
Steenhard, Brooke M; Isom, Kathryn S; Cazcarro, Patricia et al. (2005) Integration of embryonic stem cells in metanephric kidney organ culture. J Am Soc Nephrol 16:1623-31

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