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.
Hemodialysis requires a well-functioning arteriovenous fistula (AVF), but ~50% of AVFs fail within 2 years and their reconstruction is very costly (~$1 billion/y) To identify why AVF failure is so commonly, we created a model of AVF in mice to evaluate the influence of kidney failure and take advantage of mouse genetic models. Our proposal builds on new information that implicates specific molecular mechanisms leading to AVF failure suggesting potential therapeutic targets.
|Woodard, Lauren E; Cheng, Jizhong; Welch, Richard C et al. (2017) Kidney-specific transposon-mediated gene transfer in vivo. Sci Rep 7:44904|
|Dong, Yanjun; Yang, Min; Zhang, Jing et al. (2016) Depletion of CD8+ T Cells Exacerbates CD4+ T Cell-Induced Monocyte-to-Fibroblast Transition in Renal Fibrosis. J Immunol 196:1874-81|
|Luo, Jinlong; Liang, Anlin; Liang, Ming et al. (2016) Serum Glucocorticoid-Regulated Kinase 1 Blocks CKD-Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3. J Am Soc Nephrol 27:2797-808|
|Liu, Yan; Wang, Ying; Shi, Hongtao et al. (2015) CARD9 mediates necrotic smooth muscle cell-induced inflammation in macrophages contributing to neointima formation of vein grafts. Cardiovasc Res 108:148-58|
|Luo, Jinlong; Liang, Ming; Mitch, William E et al. (2015) FSP-1 Impairs the Function of Endothelium Leading to Failure of Arteriovenous Grafts in Diabetic Mice. Endocrinology 156:2200-10|
|Liang, Ming; Woodard, Lauren E; Liang, Anlin et al. (2015) Protective role of insulin-like growth factor-1 receptor in endothelial cells against unilateral ureteral obstruction-induced renal fibrosis. Am J Pathol 185:1234-50|
|Liang, Ming; Wang, Yun; Liang, Anlin et al. (2015) Migration of smooth muscle cells from the arterial anastomosis of arteriovenous fistulas requires Notch activation to form neointima. Kidney Int 88:490-502|
|Liang, Ming; Wang, Yun; Liang, Anlin et al. (2015) Impaired integrin ?3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice. Arterioscler Thromb Vasc Biol 35:607-15|
|Liang, Ming; Liang, Anlin; Wang, Yun et al. (2014) Smooth muscle cells from the anastomosed artery are the major precursors for neointima formation in both artery and vein grafts. Basic Res Cardiol 109:431|
|Wang, Yun; Liang, Anlin; Luo, Jinlong et al. (2014) Blocking Notch in endothelial cells prevents arteriovenous fistula failure despite CKD. J Am Soc Nephrol 25:773-83|
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