Role of VEGF in Glomerular Endothelial Health & Diseases

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DESCRIPTION (provided by applicant): Glomerular endothelial damage plays an important role in the pathogenesis of several proteinuric renal disorders such as preeclampsia (PE), thrombotic microangiopathic purpuras (TTP), renal transplant rejection and various endocapillary glomerulonephritides. However, the mechanisms of endothelial damage and proteinuria in these disorders are poorly understood. It has been shown that vascular endothelial growth factor (VEGF) is not only an essential molecule for glomerulogenesis and kidney development, but also important for glomerular capillary repair in experimental models of glomerular disorders such as glomerulonephritides and TTP. VEGF is also abundantly expressed in the adult glomerulus during nondiseased states, but its role in glomerular health and disease is unclear. Recently, we have demonstrated that excess placental production of sFIt-1 (a circulating VEGF antagonist) in patients with PE is responsible for proteinuria, hypertension and. qlomerular endotheliosis, the classic pathologic lesion of PE. Moreover, massive proteinuria with glomerular endotheliosis has been recently described in glomerular podocyte-specific VEGF knockout mice. Additionally, VEGF signaling inhibitors usage in clinical cancer trials have resulted in proteinuria and hypertension in humans. Therefore, we hypothesize that VEGF and its receptors play an important role in not only maintaining glomerular endothelial health but also in maintaining normal glomerular integrity and the barrier to proteinuria. Disruption of VEGF signaling by antagonists may result in proteinuria in the short term and glomerulosclerosis in the long term. In this proposal, we will first characterize our sFIt-1 induced model of proteinuria and endotheliosis to understand the mechanisms of proteinuria in VEGF-deficient states. We will then elucidate the VEGF signaling pathways that mediate the barrier against proteinuria and maintain endothelial health using chimeric VEGF receptors in glomerular endothelial cell culture studies in vitro to be followed by definitive in vivo studies in rats using VEGF receptor agonists (such as placental growth factor that activates only Fit-1 and not FIk-l) and neutralizing antibodies against various VEGF receptors. We will then study the long-term renal and vascular consequences of VEGF blockade in rats specifically seeking the development of glomerulosclerosis and hypertension. Finally, we will study the effects of VEGF inhibitors and VEGF agonists in anti-Thyl.1 nephritis, a well-characterized experimental model of glomerulonephritis, in which capillary repair is thought to be important for the resolution of nephritis. Together, these studies will facilitate us to achieve our goal of understanding the role of VEGF and glomerular endothelial cell dysfunction in the pathogenesis of proteinuria and may lead to novel therapeutic options for glomerular endothelial diseases as well as clarify the renal toxicity profile of VEGF signaling inhibitors being developed for other diseases such as cancer.