PKD1-Fibrillin Interactions and TFG-b Signaling Pathways

Johns Hopkins University, Baltimore MD

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Abstract

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