Abstract
Chronic kidney disease (CKD) causes anemia by renal damage. In CKD, the kidney is submitted to hypoxia, persistent inflammation, leading to fibrosis and permanent loss of renal function. Human recombinant erythropoietin (rEPO) has been widely used to treat CKD-associated anemia and is known to possess organ-protective properties that are independent from its well-established hematopoietic effects. Nonhematopoietic effects of EPO are mediated by an alternative receptor that is proposed to consist of a heterocomplex between the erythropoietin receptor (EPOR) and the beta common receptor (βcR). The present study explored the effects of rEPO to prevent renal fibrosis in adenine-induced chronic kidney disease (Ad-CKD) and their association with the expression of the heterodimer EPOR/βcR. Male Wistar rats were randomized to control group (CTL), adenine-fed rats (Ad-CKD), and Ad-CKD with treatment of rEPO (1050 IU/kg, once weekly for 4 weeks). Ad-CKD rats exhibited anemia, uremia, decreased renal function, increased infiltration of inflammatory cells, tubular atrophy, and fibrosis. rEPO treatment not only corrected anemia but reduced uremia and partially improved renal function as well. In addition, we observed that rEPO diminishes tubular injury, prevents fibrosis deposition, and induces the EPOR/βcR heteroreceptor. The findings may explain the extrahematopoietic effects of rEPO in CKD and provide new strategies for the treatment of renal fibrosis in CKD.
Highlights
Chronic kidney disease (CKD) is currently defined as a progressive and irreversible decline in glomerular filtration rate (GFR) below 60 mL/min per 1.73 m2 of body surface
Renal fibrosis is a major contributor to the development of CKD, and given the significance of erythropoietin receptor (EPOR)/β common receptor (βcR) heterodimer in EPO-conferred nonhematopoietic protection, in the present study, we aimed to investigate how the process of tubulointersticial fibrosis can be influenced by the coexpression of the EPOR/βcR heterodimer and the administration of recombinant erythropoietin (rEPO) in adenine-induced chronic kidney disease (Ad-CKD) model
Adenine-induced CKD was manifested in rats by metabolic and hematologic changes and kidney function decline that was ameliorated by rEPO treatment
Summary
Chronic kidney disease (CKD) is currently defined as a progressive and irreversible decline in glomerular filtration rate (GFR) below 60 mL/min per 1.73 m2 of body surface. Irrespective of the underlying cause, the series of events that lead to end-stage kidney disease, and the need for replacement therapy, are an initial injury by hypoxia or toxins, followed by chronic inflammation, oxidative stress, vascular remodeling, and tubular and glomerular fibrosis [1]. It is estimated that 10-15% of the population in industrialized countries develop some degree of CKD [2]. The burden of this disease and its complications pose a growing problem to society as the incidence of CKD increases at an annual rate. In addition to addressing the causes of CKD, a higher understanding of the pathophysiological mechanisms that underlie progression of the disease needs to be achieved
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