VEGF And Renal Inflammation

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DESCRIPTION (provided by applicant): 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.