Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of (monogenic) inherited renal failure in the United States [1]. Although the disease is named for its most notable feature, namely kidney cysts, vascular complications are in fact a significant cause of morbidity and mortality [2]. Based on the association of aneurysms and ADPKD it has been speculated that polycystins (PKD proteins) play an important role in maintaining the integrity of blood vessels [3]. In support of this hypothesis, animals with mutations in either PKD gene die in utero and often exhibit hemorrhage with leaky blood vessels and edema [4]. Despite the significance of this problem, the precise cellular function of polycystins in the vasculature has not yet been defined. We believe that exciting new clues may come from the relationship between PKD and """"""""overlap"""""""" connective tissue diseases such as Marfan syndrome (MFS) that also have a prominent vascular phenotype. Marfan syndrome is caused almost exclusively by mutations in Vnefibrillin-1 (FBN1) gene whose protein product is a major component of the extracellular matrix (ECM) in a variety of organs including blood vessels [5]. Until recently it was assumed that the pathogenic mechanism underlying the MFS phenotype had to do with a structural failure of the ECM. However recent work suggests that over activity of the TGF-p signaling pathway may play a critical role in disease pathogenesis [6]. The observation that families with ADPKD and MFS have overlapping clinical features prompted us to test for a functional interaction between the two gene products. Our preliminary studies demonstrate that mice, which are heterozygous for mutations in Pkd1 and Fbn1, have a remarkable increase in aortic wall pathology as well as evidence of increased TGF-p signaling. This application seeks to define the mechanism that is responsible for this genetic interaction and to explore the relationship between PKD1 and TGF-p related signaling pathway. We anticipate that this work will provide novel insights into the vascular complications that are associated with ADPKD. The expectation is that a better understanding of the vascular signaling pathways that are disrupted in PKD will ultimately result in rational therapeutic approaches that could be applied to the treatment and/or prevention of some of the most devastating consequences of this disease.
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