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-b1 (TGF-b1), 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-b1 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-b1. 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.

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

“…Under the control of oxygen‐sensing hypoxia inducible factor (HIF) pathway (Yi & Hak, 2012), EPO is predominantly produced by the interstitial fibroblasts of the renal cortex and outer medulla in adult animals, and by Kuffer's cells in the liver during embryonic development (Tan, Eckardt, & Ratcliffe, 1991). It has been widely used to treat chronic renal‐failure patients with anemia for many years in clinic (Teixeira et al., 2010). Recently, apart from its principal function in erythropoiesis, nonhematopoietic functions of EPO such as angiogenic, cardioprotective, and neuroprotective effects have attracted extensive concerned (Kertesz, Wu, Chen, Sucov, & Wu, 2004; Kumral et al., 2011; Tada et al., 2006).…”

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

“…This result suggests that other pathways should play a major role on the proproliferative profile encountered in this model, previously demonstrated by us through the increment in the trophism of both tissues, as well as through the increased levels of serum TGF-b1. [13] rhEPO treatment, accordingly, did not modify the expression of both genes in the CRF rats. However, rhEPO was able to exacerbate the effect of CRF on PCNA expression, thus demonstrating a proliferative action associated with DNA synthesis and repair, which are known functions of PCNA,[4445] thus suggesting a regenerative function of rhEPO in this tissue.…”

“…The remnant kidney presented a reasonable degree of functionality, mainly due to hypertrophic compensation, and there was several important cardiovascular modifications, including hypertension, tachycardia, dyslipidemia, erythropoietic disturbances, sympathetic activation, proliferation, angiogenesis, and oxidative stress, which are features seen in CKD patients. [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.…”

“…[3940] In our study, CRF was not associated with significant changes on the inflammatory markers, viewed by normal gene profile of both TNF-a and NF-κb in the heart, which is in agreement with our previous assays in serum markers of inflammation. [11–13] However, the IL-2 gene overexpression was prevented with rhEPO, suggesting an inhibitory effect on T-cell-induced IL-2 production. Previous studies on CKD patients have shown serum IL-2 increment when compared with controls,[4142] an effect that was reduced by rhEPO treatment, demonstrating that rhEPO has an immunomodulatory action.…”

“…[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.…”