Abstract & Background 

Erythropoietin (EPO) administration in uremic rats leads to an increase in blood pressure (BP).

Because chronic renal failure has been associated with oxidative stress, we hypothesize that EPO treatment could accentuate this condition and contribute to hypertension.

The present study was designed to investigate the role of reactive oxygen species in EPO-induced hypertension and the effect of tempol, a superoxide dismutase-mimetic.

Renal failure was induced by a two-stage 5/6 nephrectomy followed by a 3-week stabilization period.

Uremic rats were divided into four groups and received for 4 weeks:

• vehicle;
• EPO (100 U/kg, subcutaneously,
• three times per week); vehicle + tempol (1 mmol/l in drinking water);
• and EPO + tempol.

Systolic BP and biochemical parameters were assessed before and at the end of the treatment.

Renal histology, creatinine clearance rate, endothelin-1 (ET-1) concentrations and superoxide anion production were assessed at the end of the study.

The uremic rats developed anemia and hypertension. ET-1 concentrations and superoxide anion production were increased.

EPO administration corrected anemia, but accentuated hypertension and renal injuries such as glomerulosclerosis, interstitial fibrosis, and inflammation.

EPO therapy further increased tissue levels of ET-1 and superoxide anion production.

Tempol treatment improved hypertension and renal injury, and reduced ET-1 concentrations and superoxide anion production.

Oxidative stress contributes to the development of hypertension and to the progression of renal injuries in uremic rats. EPO administration further increases oxidative stress, which might partly account for the accentuation of hypertension and renal injury.

The availability of human recombinant erythropoietin (EPO) using molecular cloning technologies revolutionized the management of renal anemia.

Indeed, EPO replacement therapy in renal failure patients was accompanied by positive clinical effects such as reduced need for routine blood transfusions, increased exercise tolerance and enhanced quality of life.

However, correcting anemia with EPO administration in chronic renal failure may lead to the accentuation of existing hypertension or the development of de novo hypertension.^1,2

Interestingly, the pressor effect induced by EPO appears to occur almost exclusively in uremic patients.

Hypertension has not been reported in clinical trials in which EPO was administered in cases of nonrenal anemia³ or in healthy volunteers.⁴

Similarly, in renal failure rats (5/6 nephrectomy), EPO administration induced hypertension,^5,6 whereas control rats remained normotensive.^6,7

The causes leading to the development of this iatrogenic form of hypertension is still unclear.

The potential mechanisms include inappropriate increase in peripheral vascular resistance,² enhanced tissue renin–angiotensin activity,^8,9 resistance to nitric oxide (NO),⁵ and increase in vascular concentrations of endothelin-1 (ET-1).¹⁰

In the rat remnant kidney model, ET-1 levels were reported increased in blood vessels and in the renal cortex.¹¹

In addition, the increased urinary ET-1 concentrations correlated positively with elevated blood pressures (BPs), proteinuria, and glomerular sclerosis.¹²

The administration of EPO induced a further increase in vascular ET-1 production^10,13 and ET_A receptor blockade prevented the progression of hypertension in EPO-treated animals,^10,14

whereas ET_B receptor deficiency accentuated EPO-induced hypertension.⁷

Under normal condition, the in vivo vascular production and pressor effect of ET-1 are compensated by the effect of the endothelium-derived relaxing factor NO.¹⁵

In chronic renal failure, however, the production of NO is impaired.¹⁶

This could be due, at least in part, to the accumulation in plasma of NO synthase inhibitors such as asymmetric dimethylarginine.¹⁷

• Indeed, Vaziri et al.¹⁸ showed enhanced reactive oxygen species-mediated NO inactivation, protein nitration, functional NO deficiency, and hypertension in chronic renal failure.
• Administration of tempol, a membrane-permeable super oxide dismutase-mimetic, improved hypertension, and increased urinary NO metabolites in uremic rats.¹⁸
• The effect of EPO administration on reactive oxygen species production in uremia and its role in EPO-induced hypertension are unknown.

The present study was designed to investigate the involvement of reactive oxygen species in EPO-induced hypertension in renal failure animals.

We specifically studied the effect of the superoxide dismutase–mimetic tempol on BP, renal injuries, ET-1 concentrations, and superoxide production in uremic rats treated with EPO.

Marie-Eve Rancourt^1,2, Marie-Eve Rodrigue^1,2, Mohsen Agharazii^1,2, Richard Larivière^1,2 and Marcel Lebel^1,2

• ¹CHUQ Research Center, L'Hôtel-Dieu de Québec Hospital, Quebec City, Quebec, Canada
• ²Department of Medicine, Université Laval, Quebec City, Quebec, Canada

Correspondence: Marcel Lebel, (marcel.lebel@crhdq.ulaval.ca)