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.

Mycobacterium bovis, the causative agent of bovine tuberculosis (TB), is a successful pathogen that remains an important global threat to livestock. Cattle naturally exposed to M. bovis normally become reactive to the M. bovis-purified protein derivative (tuberculin) skin test; however, some individuals remain negative, suggesting that they may be resistant to infection. To better understand host innate resistance to infection, 26 cattle from herds with a long history of high TB prevalence were included in this study. We investigated the bactericidal activity, the production of reactive oxygen and nitrogen species and the TB-related gene expression profile after in vitro M. bovis challenge of monocyte-derived macrophages from cattle with TB (n=17) and from non-infected, exposed cattle (in-contacts, n=9). The disease status was established based on the tuberculin skin test and blood interferon-gamma test responses, the presence of visible lesions at inspection on abattoirs and the histopathology and culture of M. bovis. Although macrophages from TB-infected cattle enabled M. bovis replication, macrophages from healthy, exposed cattle had twofold lower bacterial loads, overproduced nitric oxide and had lower interleukin (IL)-10 gene expression (P⩽0.05). Higher mRNA expression levels of inducible nitric oxide synthase, C-C motif chemokine ligand 2 and IL-12 were observed in macrophages from all in-contact cattle than in macrophages from their TB-infected counterparts, which expressed more tumour necrosis factor-α; however, the differences were not statistically significant owing to individual variation. These results confirm that macrophage bactericidal responses have a crucial role in innate resistance to M. bovis infection in cattle.