The inability of arteriovenous fistulas (AVFs) to mature sufficiently for adequate dialysis is a major clinical problem confronting chronic hemodialysis. Up to 60% of newly created AVFs fail to mature, and currently there is no effective strategy to enhance AVF maturation. AVF maturation failure results from an imbalance between inward remodeling due to venous neointimal hyperplasia and outward remodeling due to sustained venous dilation. Although inward remodeling has been intensively studied, the contribution of outward remodeling to AVF maturation remains largely unexplored. Effective strategies for enhancing AVF maturation should promote sustained venous dilation while inhibiting hyperplasia. Therefore, it is critically important to identify therapeutic targets that modulate both processes. MicroRNAs (miRs) are crucial modulators in cardiovascular health and diseases, and miR-targeting strategies have been shown to be promising diagnostics and therapeutics in these diseases. However, the role of miRs in modulating AVF maturation has not been explored. We have generated novel results suggesting that microRNA-92a (miR-92a), a key regulator in vascular homeostasis, is a major contributor to pathological AVF remodeling. Accordingly, this project aims to determine the causal role of increased miR-92a in driving AVF maturation failure, and to investigate the efficacy of miR-92a inhibition by targeted nanomedicine in enhancing AVF maturation. Our over-arching hypothesis is that upregulation of endothelial miR-92a by chronic kidney disease (CKD) and AVF-associated aberrant blood flow causes maturation failure through two mechanisms, i.e., impairing vasodilation (outward remodeling) and promoting neointimal hyperplasia (inward remodeling). To test this hypothesis, we propose three Specific Aims.
These aims use genetic approaches and targeted nanotechnology to systematically determine the causal role of miR-92a in AVF maturation failure, advancing from miR-92a in the whole body to the inflamed endothelium.
Specific Aim 1 is to determine the causal role of miR-92a in pathological AVF development in mice with CKD. We will create AVF in whole-body miR-92a knockout and wild-type mice with CKD, and determine whether systemic knockout results in greater outward and less inward AVF remodeling.
Specific Aim 2 is to investigate whether AVF development is impaired in transgenic mice overexpressing endothelial miR-92a. We will create AVF in mice overexpression endothelial miR-92a and in control mice, and determine whether transgenic mice have impaired outward and exaggerated inward AVF remodeling.
Specific Aim 3 is to investigate the therapeutic potency of miR-92a inhibition by inflamed-endothelium targeting nanomedicine in enhancing AVF development in rats with CKD. We will determine whether nanoparticles that target inflamed ECs and contain miR-92a inhibitors can promote outward and inhibit inward AVF remodeling in rats with CKD. These studies are expected to identify the novel role of the important miR-92a pathway in the pathogenesis of AVF maturation failure. Our results will provide the first cause-and-effect evidence linking miR- 92a to AVF maturation failure, and provide an important rationale for developing innovative therapeutics that aims to target miR-92a to enhance AVF maturation, a huge unmet clinical need.
The goal of the proposed research is directly relevant to the VA's commitment to deliver high-quality, cost- effective hemodialysis care to Veterans with end-stage renal disease (ESRD). Approximately 200,000 Veterans enrolled in the VA Healthcare System have moderate to severe chronic kidney disease, among which approximately 35,000 have ESRD. Over 80% of Veterans with ESRD utilize hemodialysis as their primary renal replacement modality. Vascular access complications remain a major cause of morbidity and healthcare costs for chronic hemodialysis patients. The arteriovenous fistula (AVF) is the preferred mode of vascular access, but many newly created AVFs do not mature to become useful for dialysis. This proposal will improve our understanding of the pathophysiology of AVF maturation failure, which will potentially lead to new remedial therapies for this clinical problem and ultimately improve morbidity and mortality for the VA ESRD patients receiving new AVFs for hemodialysis therapy.