Effect of Recombinant Human Erythropoietin in a Rat Model of Moderate Chronic Renal Failure - Focus on Inflammation, Oxidative Stress and Function/Renoprotection

Abstract

Background/Aims: Chronic renal failure (CRF) patients develop anaemia, thus promoting cardiovascular complications, which seems to be favoured by the low kidney erythropoietin (EPO) production. The renal insufficiency degree might determine the moment to start recombinant human EPO (rhEPO) therapy. It has been attributed important non-hematopoietic effects to rhEPO, which might underlie cardio and renoprotection. This work aimed to evaluate the effect of rhEPO in a rat model of moderate CRF, focusing on inflammation, oxidative stress and function/renoprotection. Methods: Four groups (n=7) of male Wistar rats were evaluated during a 15 week follow-up period: control (without treatment); rhEPO (50 IU/Kg/wk Recormon ®); CRF and CRF+rhEPO. Blood samples were collected at the beginning and 3, 9 and 12 weeks after nephrectomy, in order to evaluate: renal function, haematological parameters, iron metabolism and serum proliferative (TGF-1), inflammatory (TNF-, CRP, IL-2 and IL-1) and redox status (MDA, TAS and 3-NT) markers. Kidney gene expression of Il2, Vegf, Nos2 and Nos3 were assessed by real-time PCR. Blood pressure, heart rate and tissues trophy indexes were also estimated. Results: Our data are consistent with a sustained moderate degree of CRF with development of moderate and corrected anaemia and hypertension. The remnant kidney showed a proliferative profile, with increased mass (hypertrophism), upregulated tissue Vegf gene expression, accompanied by increased levels of serum TGF-1. Serum 3-NT was augmented, suggesting oxidative stress, which was accompanied by a trend to higher kidney Nos gene expression of both isoforms. rhEPO treatment was able to partially attenuate renal function markers, totally correct anaemia, also demonstrating a proliferative and antioxidant action, suggesting renoprotection. Conclusion: This study suggests that rhEPO therapy might be recommended in moderate CRF stages in order to efficiently correct not only the anaemia but also the underlying deleterious mechanisms, due to a proliferative and antioxidant action on the remnant kidney.

Cardiac antiapoptotic and proproliferative effect of recombinant human erythropoietin in a moderate stage of chronic renal failure in the rat

“…[ 11 – 13 ] The use of rhEPO in that model showed interesting cardiorenal effects, including prevention of tachycardia, of catecholamines increment and of dyslipidemia, together with a notorious proproliferative action on the remnant kidney and on the heart tissue. [ 12 ] Considering that EPO interaction with its receptor leads to activation of several important pathways related with apoptosis, proliferation, angiogenesis, inflammation, and lesion/stress, we hypothesize that the putative cardioprotective effect of early rhEPO use might be linked with adaptations on heart gene expression. [ 15 – 17 , 21 ]…”

“…Considering that the use of human tissues is obviously limited by ethical reasons, our group has previously extensively characterized a model of moderate CRF,[ 11 ] in which rhEPO treatment has promoted erythrocytosis and prevented tachycardia, catecholamines increment and dyslipidemia, with a rise of serum TGF-b1. [ 12 13 ] Thus, rhEPO therapy, under these circumstances, has promoted a beneficial effect on the cardiac tissue, which might be attributed to its protective actions, namely of proproliferative and antiapoptotic nature, as was previously suggested in other conditions and pathologies,[ 3 – 6 ] but that deserves a more extensive evaluation, particularly in moderate stages of CKD, before critical impairment of the kidney and heart tissues.…”

“…[1213] Thus, rhEPO therapy, under these circumstances, has promoted a beneficial effect on the cardiac tissue, which might be attributed to its protective actions, namely of proproliferative and antiapoptotic nature, as was previously suggested in other conditions and pathologies,[3–6] but that deserves a more extensive evaluation, particularly in moderate stages of CKD, before critical impairment of the kidney and heart tissues.…”

Recombinant Human Erythropoietin: Manfaat dalam Bidang Kedokteran

“…Penelitian aktivitas rhEPO telah banyak dilakukan dengan menggunakan kultur sel berdasarkan berbagai macam cell lines seperti Erythropoietin-dependent human leukemia (AS-E2), human erythroleukaemia TF1, dan megakaryocytic cell line UT-7 (Miyazaki et al, 1997;Qiu et al, 1998) (Eder et al, 1989;Choi et al, 1996). Garrido et al (2010) Dalam dunia kedokteran hewan rhEPO juga telah dimanfaatkan untuk pengobatan kasus gagal ginjal akut dan kronis pada anjing dan kucing (Boran et al, 1993). Menurut Bugelski et al (2008) (Mikiciuk et al, 1990;Cowgill, 1991;Giger, 1992;Langston et al, 2003) (Chalhoub et al, 2011;Chew et al, 2011).…”

Hot Topic: [Potential therapeutic use of recombinant human erythropoietin (Guest Editor: Elisio Costa)]

“…Finally, this supplement include an original article [14] that intend to study the effect of rhEPO on inflammation, oxidative stress and renal function/renoprotection, by using a rat model of moderate renal failure. We hope that this supplement could be useful to stimulate more research in this area, particularly concerning to robust clinical trials in non-anaemic patients.…”