The development of blood vessels is a major event in kidney morphogenesis, however, the molecular basis of kidney vascularization is unknown. A role for soluble angiogenic factors has been postulated.. Vascular endothelial growth factor (VEGF) is the best candidate for such a role because it is a secreted direct acting endothelial cell mitogen required for vasculogenesis. The hypotheses to be tested are: 1) VEGF mediates glomerular vascularization, and 2) hypoxia regulates VEGF-mediated angiogenesis. To address the first question, we will define the effect of VEGF on kidney organ culture and we will identify VEGF target cells using VEGF receptors antibodies and beta-gal staining of FIK-1(+/-) transgenic explants. To test the second hypothesis, cultured kidneys will be exposed to hypoxia and endothelial cell differentiation and proliferation will be assessed by morphologic studies. VEGF role mediating these events will be defined using anti-VEGF neutralizing antibodies. These experiments will be performed using fetal rats and FIK-1(+/-)transgenic mice. We will identify and clone transcription factors involved in VEGF regulation by hypoxia using an expression library constructed ad hoc from hypoxic kidneys, screened with O2 sensitive DNA probes and differential display PCR amplification of mRNAs from hypoxic and control explants. The combination of histochemical, molecular biology and transgenic technology will enable us to determine the origin of renal endothelial cells and to define the role of VEGF in kidney vascularization. Understanding the molecular mechanisms governing vasculogenesis and angiogenesis should generate new strategies for prevention, diagnosis and treatment of renovascular disease and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002421-05
Application #
6329245
Study Section
Special Emphasis Panel (SRC)
Program Officer
Schucker, Beth
Project Start
1996-12-01
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2002-11-30
Support Year
5
Fiscal Year
2001
Total Cost
$121,230
Indirect Cost
Name
University of Virginia
Department
Pediatrics
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Tufro, Alda; Veron, Delma (2012) VEGF and podocytes in diabetic nephropathy. Semin Nephrol 32:385-93
Villegas, Guillermo; Tufro, Alda (2002) Ontogeny of semaphorins 3A and 3F and their receptors neuropilins 1 and 2 in the kidney. Mech Dev 119 Suppl 1:S149-53
Villegas, Guillermo; Tufro, Alda (2002) Ontogeny of semaphorins 3A and 3F and their receptors neuropilins 1 and 2 in the kidney. Gene Expr Patterns 2:151-5
Tufro, A (2000) VEGF spatially directs angiogenesis during metanephric development in vitro. Dev Biol 227:558-66