Effects of Recombinant Human Erythropoietin on Resistance Artery Endothelial Function in Stage 4 Chronic Kidney Disease

Abstract

BackgroundRecent studies have raised concern about the safety of erythropoiesis‐stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. In the present study, we investigated the effects of recombinant human erythropoietin (EPO) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m2) aged 63±13 years.Methods and ResultsArteries were mounted on a pressurized myograph. EPO impaired endothelium‐dependent relaxation in a concentration‐dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO (P<0.001). EPO‐induced endothelial dysfunction was significantly associated with carotid stiffness and history of cardiovascular events. EPO had no effect on norepinephrine‐induced vasoconstriction or sodium nitroprusside–induced relaxation. ABT‐627, an endothelin type A receptor antagonist, and tempol, a superoxide dismutase mimetic, partially reversed the altered endothelial function in the presence of EPO (P<0.01). Increased expression of endothelin‐1 was found in the vessel wall after incubation with EPO.ConclusionsEPO alters endothelial function of resistance arteries in CKD patients via a mechanism involving in part oxidative stress and signaling through an endothelin type A receptor. EPO‐induced endothelial dysfunction could contribute to deleterious effects of EPO described in large interventional trials.

Erythropoietin-induced hypertension and vascular injury in mice overexpressing human endothelin-1

“…Experimental animals and patients with CKD present increased ET-1 expression, which is enhanced by erythropoietin [16][17][18]. This study demonstrates that erythropoietin-induced BP rise and adverse vascular effects were dependent on preexisting increased ET-1 expression.…”

“…Data from previous studies suggest a role for increased ET-1 expression in erythropoietin-induced hypertension and cardiovascular events. An ET A R antagonist prevented erythropoietin-induced exaggeration of BP rise in rats with CKD [17] and reduced erythropoietin-induced impairment of endothelial function in human resistance arteries [18]. It is noteworthy that increased ET-1 expression is not sufficient to cause BP elevation.…”

“…Previous studies have demonstrated that oxidative stress plays a role in erythropoietin-induced hypertension and vascular injury. Tempol prevented erythropoietininduced exaggeration of BP rise and progression of renal injury in rats with CKD [16] and prevented erythropoietininduced impairment of endothelial function in human resistance arteries [18]. However, by itself, oxidative stress is not sufficient to elevate BP and induced endothelial dysfunction.…”

“…EPO-induced exaggeration of hypertension, but not anaemia correction, was prevented by a selective ET type A receptor (ET A R) antagonist or the superoxide dismutase mimetic tempol. Recently, we showed in vitro that EPO dose-dependently reduced acetylcholine-induced relaxation and increased expression of ET-1 and ET A R in gluteal subcutaneous resistance arteries from stage 4 CKD patients [18]. An ET A R antagonist and the antioxidant tempol reduced or prevented EPO-induced impairment of endothelial function.…”

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

“…While hypertensive effects of rhEPO therapy are well established, underlying mechanisms are not well understood. Endothelin-1 27-29 , and thromboxane 30 each has been implicated as rhEPO-modulated vasoconstrictors. Possible contributions of blood cell volume changes or viscosity effects, in contrast, have largely been discounted, 25, 26 with transfusions and rhEPO dosing similarly affecting viscosity but not blood pressure.…”