There are nearly 90,000 patients with end-stage renal disease in Taiwan and approximately 90% of them on hemodialysis. Autogenous arteriovenous (AV) fistula is the access of choice but only 60% of AV fistulas remain functional at 12 months. The most common cause of early fistula failure is venous stenoses near the AV anastomosis. The pathology of stenosis is predominantly intimal hyperplasia, characterized by an abundance of smooth muscle cells, myofibroblasts, and macrophages. The intimal hyperplasia narrows the venous outflow, and eventually leads to stenosis or subsequent thrombosis. Intimal hyperplasia develops preferentially at sites of arteriovenous anastomosis, largely owing to the disturbed flow pattern characterized by low shear stress amplitudes, high oscillatory shear index and steep temporal/spatial shear stress gradient. Nonetheless, the molecular mechanisms linking disturbed flow, endothelial dysfunction and intima hyperplasia remain unclear. We have recently identified an endoplasmic reticulum (ER)-resident protein thioredoxin domain containing 5 (TXNDC5) as a pivotal mediator of disturbed flow related endothelial dysfunction. The expression of TXNDC5 was markedly upregulated in human aortic endothelial cells (HAEC) upon exposure to disturbed flow. The expression level of endothelial TXNDC5 positively correlated with TNFRSFs and TGF-1, and negatively correlated with factors KLF2 and KLF4. Knocking down TXNDC5 in HAEC increased eNOS expression. In stenotic tissues from failed AV fistulas of hemodialysis patients, we observed an abundant TXNDC5 expression in the neointima area. Global deletion of TXNDC5 in mice significantly reduced neointima volume after AV fistula creation. Taken together, these data suggest an important yet unrecognized role of TXNDC5 in the pathogenesis of endothelial dysfunction and intimal hyperplasia induced by disturbed flow.The goal of this proposal is to elucidate the molecular mechanisms linking TXNDC5 and venous intimal hyperplasia in dialysis AV fistulas. First, we will determine if TXNDC5 mediates endothelial dysfunction in human umbilical vein endothelial cell culture (HUVEC) after exposure to unidirectional or disturbed flow by a dynamic device. The molecular pathway between disturbed flow, TXNDC5, and endothelial dysfunction will be clarified in the in vitro study. Second, we will determine the in vivo contribution of TXNDC5 to venous intimal hyperplasia after AV fistula creation by TXNDC5 knock-out mice. The role of endothelial TXNDC5 in will be elucidated by cell linage-specific deletion of TXNDC5. Finally, we will test the hypothesis that targeting TXNDC5 in vivo using pharmacological agents and DNA aptamers could mitigate venous intima hyperplasia. The results from this proposal will provide novel insights into the pathogenesis of venous intima hyperplasia of dialysis AV fistulas and may lead to the development of novel therapeutic approach to facilitate maturation of dialysis AV fistulas.
end stage renal disease
endoplasmic reticulum-resident protein