CHRONIC KIDNEY DISEASE ADVERSELY INFLUENCES VASCULAR FUNCTIONS

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DESCRIPTION (provided by applicant): Our long-term goal is to identify how chronic kidney disease (CKD) influences the cellular and molecular mechanisms underlying arteriovenous fistula (AVF) failure in patients with CKD. For many patients with CKD, hemodialysis is the preferred method of treatment; there are ~470,000 patients receiving hemodialysis treatments in U.S. The success of hemodialysis treatments requires a functioning arteriovenous access (AVF). However, in the 2 years following creation of the AVF, nearly 50% of the fistulas fail, generally due to neointima hyperplasia of vascular smooth muscle cells (SMCs). The costs of preventing or correcting AVF failure exceed $1 billion per year! Therefore, understanding the mechanisms underlying the development of the neointima could lead to a directed therapeutic strategy. We created a model of AVF in CKD mice that mimics events occurring in patients. In mice with CKD, we have uncovered clues to neointima formation in AVF. First, there is increased expression of FSP-1 in BM cells and FSP-1-positive cells and inflammatory cells in our mouse model of AVFs. Second, there is evidence of endothelial-mesenchymal transition (EnMT) in failed AVFs from CKD patients. Third, CKD activates Notch signaling and specifically, the RBP- J: transcription factor. Thus, we hypothesize that CKD-induced activation of Notch/RBP-J that promotes EnMT resulting in endothelial barrier dysfunction with infiltration of inflammatory and BM cells, leading to neointima formation. To test our hypothesis, we will create AVF in CKD and combined it with transgenic approaches. This will allow us: 1) to determine if CKD-induced EnMT accelerates endothelial barrier dysfunction and neointima formation in AVFs. 2) To identify how BM-derived cells expressing FSP-1 increase neointima formation in AVFs during CKD. 3) To investigate if RBP-J: contributes to neointima formation in CKD. Thus, our results will directly address the mechanism by which the presence of CKD accelerates neointima formation and AVF failure. In summary, results from our proposed experiments could provide a new paradigm for understanding mechanisms underlying the clinically relevant, costly problem of the failing dialysis access related to neointima formation.