Role of oxidative stress in erythropoietin-induced hypertension in uremic rats.
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Rancourt
Marie-Eve
ME
CHUQ Research Center, L'Hôtel-Dieu de Québec Hospital, Quebec City, Quebec, Canada.
Rodrigue
Marie-Eve
ME
Agharazii
Mohsen
M
Larivière
Richard
R
Lebel
Marcel
M
D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood; D004921:Erythropoietin / Q000009:adverse effects* / Q000627:therapeutic use; D006973:Hypertension / Q000139:chemically induced*; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D014511:Uremia / Q000150:complications* / Q000473:pathology
D019332:Endothelin-1; D011994:Recombinant Proteins; D004921:Erythropoietin