The normal human kidney expresses significant amount of vascular endothelial growth factor (VEGF), the most potent angiogenic cytokine, which also has proinflammatory properties. A number of inflammatory kidney diseases are associated with VEGF-induced rich vascular network and leukocyte trafficking. The overall objective of this proposal is to explore a novel role of VEGF in renal inflammation. We have identified a mechanistic link between immune response (involving CD40 ligand, expressed on activated T cells and platelets, and CD40 interactions) and the overexpression of VEGF. The renal endothelial and epithelial cells, both express CD40.
In Specific Aim 1, the mechanistic interactions among CD40 signaling and VEGF production will be determined. The sophisticated in vitro models will be utilized to define the role of different intracellular signaling molecules, with special importance to Ras in CD40-induced VEGF overexpression in human vascular endothelial cell (HUVEC), and also in renal proximal epithelial cell (RPTEC). The mechanism of CD40-induced VEGF transcriptional activation will also be determined.
In Specific Aim 2, the VEGF-induced proinflammatory signals that regulate endothelial activation responses will be measured. The role of specific transcription factors in promoting VEGF-induced expression of the chemokine IP-10 in HUVEC will be addressed. In this respect, by the use of chimeric constructs, the role of individual receptors will be dissected. Together, these experiments should elucidate the mechanism of CD40-induced VEGF overexpression in endothelial and epithelial cells, and explore how VEGF promotes renal inflammation through the release of chemokines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK064182-04
Application #
7060067
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2003-05-15
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$125,820
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Basu, Aninda; Contreras, Alan G; Datta, Dipak et al. (2008) Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer. Cancer Res 68:5689-98
Datta, Dipak; Dormond, Olivier; Basu, Aninda et al. (2007) Heme oxygenase-1 modulates the expression of the anti-angiogenic chemokine CXCL-10 in renal tubular epithelial cells. Am J Physiol Renal Physiol 293:F1222-30
Datta, Dipak; Flaxenburg, Jesse A; Laxmanan, Sreenivas et al. (2006) Ras-induced modulation of CXCL10 and its receptor splice variant CXCR3-B in MDA-MB-435 and MCF-7 cells: relevance for the development of human breast cancer. Cancer Res 66:9509-18
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Laxmanan, Sreenivas; Datta, Dipak; Geehan, Christopher et al. (2005) CD40: a mediator of pro- and anti-inflammatory signals in renal tubular epithelial cells. J Am Soc Nephrol 16:2714-23
Flaxenburg, Jesse A; Melter, Michael; Lapchak, Peter H et al. (2004) The CD40-induced signaling pathway in endothelial cells resulting in the overexpression of vascular endothelial growth factor involves Ras and phosphatidylinositol 3-kinase. J Immunol 172:7503-9
Lapchak, Peter H; Melter, Michael; Pal, Soumitro et al. (2004) CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island. Am J Physiol Renal Physiol 287:F512-20