Translational study of RAGE-SIRT1 therapy for arteriovenous fistula maturation

Va Salt Lake City Healthcare System, Salt Lake City UT

Investigators

Abstract

Objective: In this translational research proposal, our first goal is to determine the roles of the receptor for advanced glycation end-products (RAGE) and sirtuin-1 (SIRT1) in endothelial cells (ECs) in arteriovenous fistula (AVF) maturation failure. Our second goal is to determine the efficacy of small-molecule RAGE inhibitors and SIRT1 activators in improving AVF maturation. Hypothesis: Disturbed blood flow increases RAGE and decreases SIRT1 in ECs, leading to DNA damage and senescence-associated secretory phenotype (SASP) to cause AVF maturation failure. Background: AVFs are surgically created by anastomosing a vein to a nearby artery directly, exposing the fistula vein to highly disturbed blood flow. Successful AVF maturation occurs through sufficient lumen expansion to increase AVF blood flow. The inability of AVFs to mature is a major clinical problem confronting chronic hemodialysis. Up to 60% of newly created AVFs fail to mature, and currently, there is no proven effective strategy to enhance AVF maturation. Our proposal is supported by novel and strong preliminary work from our research team pointing to a causal role of DNA damage and SASP in poor AVF remodeling, following the differing effects of disturbed flow on RAGE and SIRT1 in ECs. Aims: Aim 1 is to demonstrate the causality of endothelial RAGE and SIRT1 in DNA damage, SASP, and AVF outcomes in mice. Aim 2 is to elucidate the crosstalk between RAGE and SIRT1 in disturbed flow-induced DNA damage and SASP in endothelial cells. Aim 3 is to demonstrate the efficacy of RAGE inhibitors and SIRT1 activators in decreasing DNA damage and SASP and improving AVF outcomes in mice. Research Design: We will use a combination of animal and cell studies. Animal studies will use both genetic and pharmacological approaches to investigate how RAGE inhibition and SIRT1 activation affect AVF remodeling in mice of old age with chronic kidney disease. Cell studies will use a unique dynamic co-culture model to elucidate the crosstalk between RAGE and SIRT1 in cells of old age under AVF-mimicking disturbed flow, with a focus on DNA damage and SASP response. Significance: The knowledge gained by completing the proposed aims will help to identify novel pharmaceutical targets for the prevention/treatment of AVF maturation failure, particularly in Veterans of older age.