Elevated erythropoietin receptor and transforming growth factor-beta 1 expression in stenotic arteriovenous fistulae used for hemodialysis

The issue of whether recombinant human erythropoietin (rhEPO) increases thr ombosis of arteriovenous (AV) fistulae used for hemodialysis remains unclea r. Thrombosis often occurs at stenotic segments of fistulae where there is marked intimal hyperplasia and extracellular matrix accumulation. Increased expression of transforming growth factor-beta 1 (TGF-beta 1) has been show n to be involved in the development of atherosclerotic lesions by promoting intimal hyperplasia and extracellular matrix accumulation. To clarify the role of rhEPO in the development of stenosis of AV fistulae, this study exa mined expression of the erythropoietin receptor (EPO-R), TGF-beta 1, plasmi nogen activator inhibitor type 1 (PAI-1), cellular fibronectin containing a n extra domain A (EDA+), and TGF-beta 1 mRNA, and assessed in situ rhEPO bi nding in tissue specimens from seven cutaneous veins and eight patent and s even stenosed portions of AV fistulae of patients undergoing dialysis. Prom inent intimal hyperplasia was evident in the stenosed segments. Significant elevation in expression of EPO-R and TGF-beta 1 was noted in patent AV fis tulae compared to the cutaneous veins. Significant enhancement of EPO-R and TGF-beta expression was detected in the stenotic fistulae. Fibronectin EDA + and PAI-1 expression was increased in intimal hyperplasia compared to pat ent fistulae and cutaneous veins. Elevated EPO-R expression was further con firmed by in situ binding of biotin-labeled rhEPO in stenosed tissue specim ens. It is hypothesized that increased rhEPO binding due to elevated EPO-R expression contributes to the development of AV fistula stenosis caused by intimal hyperplasia and extracellular matrix accumulation in response to in creased TGF-beta 1 expression in patients receiving hemodialysis.