Vascular endothelial growth factor (VEGF) function is critical for vascular development. However, the molecular events that coordinate vascular development and kidney morphogenesis are unknown. VEGF is expressed in parenchymal cells contiguous to the developing kidney vasculature throughout embryonic life and postnatal life. We showed that VEGF induces vasculogenesis in metanephric organ culture and that VEGF is a chemoattractant providing direction to migrating endothelial cells during renal morphogenesis, suggesting that VEGF is important to establish the spatial organization of the renal vasculature. The molecular basis of the vascular spatial organization in the developing kidney and the function of VEGF in renal epithelial cells are unknown and are the focus of this proposal. The objective of this proposal is to elucidate the mechanisms mediating directional endothelial cell migration during kidney organogenesis and vascularization. Our hypothesis is that VECiF produced by renal epithelial cells generates local concentration gradients providing a chemoattractive cue for endothelial cell migration. We also postulate that VEGF supports the establishment and maintenance of fenestrated endothelial cell phenotype and thereby contributes to the regulation of vascular permeability. To test our hypotheses: 1) we will study the mechanism of directional endothelial cell migration towards embryonic kidneys and examine the function of the VEGF system in renal epithelial cells using migration assays and co-culture models. 2) We will study the downstream signaling mechanisms involved in VEGF-induced directional endothelial cell migration: examine the role of integrins, FAK and MAP kinase mediated signals. 3) We will determine whether VEGF is required for the establishment and maintenance of the fenestrated phenotype of glomerular endotheial cells in vitro and study the signaling mechanisms involved. The proposed experiments should provide fundamental information regarding VEGF-induced directional migration and advance our knowledge of the molecular mechanisms governing vascular spatial organization and renal morphogenesis. Understanding the molecular basis of guidance cues for cell migration should enable us to generate new strategies for diagnosis and treatment of congenital renal abnormalities and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059333-06
Application #
6863717
Study Section
Pathology A Study Section (PTHA)
Program Officer
Hoshizaki, Deborah K
Project Start
2001-05-01
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2008-02-28
Support Year
6
Fiscal Year
2005
Total Cost
$317,300
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Gee, Heon Yung; Sadowski, Carolin E; Aggarwal, Pardeep K et al. (2016) FAT1 mutations cause a glomerulotubular nephropathy. Nat Commun 7:10822
Tufro, Alda (2015) Tubular vascular endothelial growth factor-a, erythropoietin, and medullary vessels: a trio linked by hypoxia. J Am Soc Nephrol 26:997-8
Tufro, Alda (2014) Semaphorin3a signaling, podocyte shape, and glomerular disease. Pediatr Nephrol 29:751-5
Veron, Delma; Aggarwal, Pardeep K; Velazquez, Heino et al. (2014) Podocyte-specific VEGF-a gain of function induces nodular glomerulosclerosis in eNOS null mice. J Am Soc Nephrol 25:1814-24
Reidy, Kimberly J; Aggarwal, Pardeep K; Jimenez, Juan J et al. (2013) Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction. Am J Pathol 183:1156-1168
Tufro, Alda (2013) Cholesterol accumulation in podocytes: a potential novel targetable pathway in diabetic nephropathy. Diabetes 62:3661-2
Veron, Delma; Villegas, Guillermo; Aggarwal, Pardeep Kumar et al. (2012) Acute podocyte vascular endothelial growth factor (VEGF-A) knockdown disrupts alphaVbeta3 integrin signaling in the glomerulus. PLoS One 7:e40589
Tufro, Alda (2012) Morpholino-mediated gene knockdown in mammalian organ culture. Methods Mol Biol 886:305-9
Tufro, Alda; Veron, Delma (2012) VEGF and podocytes in diabetic nephropathy. Semin Nephrol 32:385-93
Veron, D; Bertuccio, C A; Marlier, A et al. (2011) Podocyte vascular endothelial growth factor (Vegf???) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia 54:1227-41

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