(Taken directly from the application) Diabetic microvascular complications are a major clinical problem that cause a variety of cardiovascular disorders including chronic renal failure, ischemic heart disease and visual disturbances. Microvascular lesions in diabetes mellitus are critically dependent upon the loss of physiological endothelial function and response. This results in enhanced platelet and neutrophil deposition, disorganized and immature neovascularization, vascular leakage, vasospasm and ischemic episodes. Therapeutic interventions that restore the endothelial dysfunction and abolish disorganized vascularization promise to provide a new approach to control of diabetic microangiopathy. Recent findings have demonstrated the pathogenic function of vascular endothelial growth factor (VEGF) and its receptors in diabetic microangiopathy at extra-renal sites. VEGF is essential for endothelial proliferation and neovascularization, and its expression is upregulated in diabetic retinas. Importantly, VEGF receptor antagonists have been shown to reduce retinopathy in animal models. Similar up-regulation of VEGF and VEGF receptors has been demonstrated in diabetic glomeruli, however, direct evidence for a functional consequence of this has not yet been provided. We have recently analyzed pdx1-HNF6 transgenic mice, in which pancreatic islet structure is specifically disorganized and insulin secretion is severely defected, and found that pdx1-HNF6 transgenics develop diabetes after birth and reveal moderate diabetic glomerular changes at an early age. Using pdx-1-HNF6 transgenic (and STZ model) and knockouts for risk factor genes of diabetic nephropathy, we will first define the determinant that influences glomerular microvascular function and VEGF/VEGF receptor expression in diabetic nephropathy. Second, using VEGF and VEGF antagonists, we will elucidate the pathological function of VEGF and explore therapeutic potential of VEGF and anti-VEGF treatment for diabetic nephropathy. These efforts will further clarify the molecular basis by which diabetes causes glomerular endothelial disorders, and elucidate roles of VEGF in diabetic nephropathy. These studies are highly integrated with other projects and core facilities of the Vanderbilt O'Brien Center and will promise future therapeutic approaches to attenuate progression of diabetic nephropathy.
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