Recombinant human erythropoietin treatment protects the cardio-renal axis in a model of moderate chronic renal failure.
Chronic kidney disease (CKD) patients develop anemia because of the low kidney erythropoietin (EPO) production, thus promoting cardiovascular complications. The degree of renal insufficiency might determine the moment to start recombinant human erythropoietin (rhEPO) therapy, but the molecular basis for these options deserves better elucidation. This study aimed to clarify the cardio-renal effects of earlier rhEPO therapy in rats with moderate chronic renal failure (CRF). Four groups of rats were evaluated for 15 weeks (control; rhEPO - 50 IU/kg/week; CRF - 3/4 nephrectomy; CRF + rhEPO) to assess renal and hematology data, EPO levels, blood pressure, heart rate, peripheral catecholamines contents, serum-transforming growth factor-β1 (TGF-β1), kidney gene expression of EPO, Caspase 9 (Casp9), and vascular endothelial growth factor (Vegf). This model of moderate CRF showed moderate and corrected anemia, hypertension, tachycardia, sympathetic overactivity, and increased serum TGF-β1 content. The remnant kidney showed a proliferative profile, with hypertrophy, downregulated gene expression of EPO, and upregulated gene expression of Vegf and Casp9. rhEPO treatment promoted erythrocytosis and prevented tachycardia and catecholamines increment, with a rise of serum TGF-β1. Furthermore, the decreased kidney gene expression of EPO and the overexpression of Casp9 were prevented, demonstrating a renoprotective action on the remnant kidney. In conclusion, rhEPO therapy promotes a protective effect on the cardio-renal axis, which might be mainly attributed to its pro-proliferative and anti-apoptotic properties. These findings might recommend its use in earlier stages of CRF, acting as an erythropoiesis stimulating agent, to efficiently correct not only the anemia, one of the major complications in these patients, but also the succeeding adverse cardio-renal effects.
Teixeira
Ana Margarida
AM
Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, Coimbra University, Coimbra, Portugal.
Garrido
Patrícia
P
Santos
Paulo
P
Alves
Rui
R
Parada
Belmiro
B
Costa
Elísio
E
Almeida
Anabela
A
Teixeira-Lemos
Edite
E
Sereno
José
J
Pinto
Rui
R
Belo
Luís
L
Santos-Silva
Alice
A
Teixeira
Frederico
F
Reis
Flávio
F
D000818:Animals; D001794:Blood Pressure; D053453:Caspase 9 / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage* / Q000378:metabolism; D006331:Heart Diseases / Q000209:etiology / Q000517:prevention & control*; D006339:Heart Rate; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D017933:Peripheral Nervous System / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy*; D013564:Sympathetic Nervous System / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D004921:Erythropoietin; C506435:Casp9 protein, rat; D053453:Caspase 9