Role of Oxidative Stress in the Pathogenesis of Erythropoietin-Induced Hypertension

C hronic kidney disease (CKD) results in anemia, which is largely due to reduced production of the renal hormone, erythropoietin (EPO). The advent of recombinant EPO, 20 years ago, revolutionized treatment of anemia in CKD population. However, its use has been associated with a number of originally unex pected side effects including hypertension (HTN), thrombosis, tumor growth, progression of renal disease, and diabetic retino pathy. It is now clear that EPO has antiapoptotic, vasoregula tory, angiogenic, hemostatic, and many other functions that are advantageous in physiological condition but can cause serious complications in patients receiving high doses of recombinant EPO (rEPO).1,2 These effects are mediated by EPO receptor, which is expressed, not only in erythroid progenitor cells but many other cell types (endothelial cells, vascular smooth muscle cell, cardiomyocytes, myoblasts, retinal photoreceptors, neu rons, hepatic stromal cells, macrophages, renal cells, most cancer cells, etc.). One of the unexpected side effects noted during the initial clinical trials of rEPO was HTN, which was occasionally associated with encephalopathy and seizures and manifested several weeks after initiation of therapy. As the rise in blood pressure (BP) frequently parallels that of hematocrit, it was conveniently attributed to improvement of anemia. However, in a series of studies, we found an equal rise in BP with rEPO therapy in ironsufficient and irondeficient CKD rats (despite persistent anemia in the latter) and no rise in BP with ane mia correction by multiple small blood transfusions in CKD animals3 or iron repletion in irondeficient CKD patients.4 Together, these observations proved that EPOinduced HTN is caused by EPO, not anemia correction. As described in recent reviews,1,2 EPO can raise BP by: (i) increasing cytosolic ionized calcium [Ca]i and expand ing sarcoplasmic calcium stores, events that cause nitric oxide (NO) resistance and raise systemic vascular resistance, (ii) raising endothelin1 production, (iii) upregulating renal and vascular tissue renin, angiotensinogen, and angiotensin receptor expressions, (iv) increasing release of vasoconstrictor (PGF2α and thromboxane) and lowering production of vasodilator (prostacyclin) prostaglandins. In a study published in the current issue of the journal, Rancourt et al.5 have demonstrated the contribution of oxi dative stress to the EPOinduced HTN in experimental CKD. They found intensification of HTN, elevation of plasma endothelin1, heightened superoxide production in the arterial tissue, and accelerated renal injury with rEPO administration in their CKD animals that were attenuated by concomitant therapy with the superoxide dismutase–mimetic drug, tempol. These findings have provided compelling evidence for contri bution of oxidative stress to EPOinduced HTN. Mounting evidence has emerged demonstrating the role of oxidative stress in the pathogenesis of HTN (review in ref. 6). Oxidative stress can raise BP by limiting production and bio availability of nitric oxide (NO) in key tissues involved in BP regulation (kidney, vascular tissue, and brain) by: inactivat ing NO, uncoupling endothelial NO synthase, depleting NOS cofactor, tetrahydrobiopterin, and inhibiting dimethylarginine dimethylaminohydrolase and upregulating protein methyl transferase1, which lead to accumulation of the NOS inhibi tor asymmetrical dimethylarginine. NO deficiency, in turn elevates BP by raising systemic vascular resistance, promot ing sodium retention, blunting pressure natriuresis, increas ing central sympathetic activity, and causing endothelial dysfunction and vascular remodeling. In addition, oxidative stress contributes to HTN by raising production of proinflam matory and vasoconstrictor by products of arachidonic acid