ADPKD is the most common life threatening hereditary disease in the USA. It affects about 1:400 to 1:1000 people. ADPKD accounts for about 5-10% of end-stage renal failure in the USA requiring dialysis and renal transplantation. The Han:SPRD rat model and mice with a targeted mutation in the Pkd2 gene closely resemble human ADPKD and present an opportunity to evaluate the therapeutic effect of agents that have the potential to interfere with one or more of the pathogenic elements of ADPKD. Angiogenesis is a feature of human polycystic kidneys and may provide the blood supply for progressive cyst formation. The effect of angiogenesis inhibition on cyst formation and subsequent renal failure is not known. One of the central components of angiogenesis is the growth factor VEGF and its receptors VEGFR-1 and VEGFR-2. VEGF receptor inhibitors have been widely used in animal studies of cancer in vivo to dramatically alter a variety of pathological processes. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby VEGF may function in an autocrine fashion to stimulate cystic epithelial cell proliferation as well as in a paracrine fashion to stimulate vascular endothelial cell proliferation and angiogenesis.
In specific aim 1, we shall characterize the angiogenesis, VEGF and VEGF receptor expression in ADPKD.
In specific aim 2 we shall use an in vitro model of cyst formation to identify the role of VEGF on cyst epithelial proliferation.
Specific aim 3 focuses on in vivo studies using VEGF receptor inhibitors. The relevance of these studies to clinical ADPKD is substantial and the results should provide leads to altering the course of ADPKD. This is particularly true because of the current availability of VEGF receptor antagonists and their proven beneficial effect in cancer studies
