title: Recombinant human erythropoietin treatment protects the cardio-renal axis in a model of moderate chronic renal failure.
abstract: 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.
authors.affiliation: Institute of Pharmacology & Experimental Therapeutics, IBILI, Medicine Faculty, Coimbra University, Coimbra, Portugal.
authors.forename: Ana Margarida
authors.initials: AM
authors.lastname: Teixeira
authors.forename: Patrícia
authors.initials: P
authors.lastname: Garrido
authors.forename: Paulo
authors.initials: P
authors.lastname: Santos
authors.forename: Rui
authors.initials: R
authors.lastname: Alves
authors.forename: Belmiro
authors.initials: B
authors.lastname: Parada
authors.forename: Elísio
authors.initials: E
authors.lastname: Costa
authors.forename: Anabela
authors.initials: A
authors.lastname: Almeida
authors.forename: Edite
authors.initials: E
authors.lastname: Teixeira-Lemos
authors.forename: José
authors.initials: J
authors.lastname: Sereno
authors.forename: Rui
authors.initials: R
authors.lastname: Pinto
authors.forename: Luís
authors.initials: L
authors.lastname: Belo
authors.forename: Alice
authors.initials: A
authors.lastname: Santos-Silva
authors.forename: Frederico
authors.initials: F
authors.lastname: Teixeira
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
mesh_terms: 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
chemical_list: 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