title: Pathological and molecular mechanisms underlying resistance to recombinant human erythropoietin therapy in the remnant kidney rat model of chronic kidney disease associated anemia.
abstract: Anemia of chronic kidney disease (CKD) can be corrected by treatment with recombinant human erythropoietin (rHuEPO); however, some patients become hyporesponsive. The molecular mechanisms underlying this resistance remain to be elucidated. Our aim was to study hyporesponsiveness to rHuEPO therapy using the remnant kidney rat model of anemia associated with CKD induced by 5/6 nephrectomy. At starting, male Wistar rats were divided in 3 groups, for a 3-week protocol: Sham, CRF (vehicle) and two rHuEPO (200 k/kg body weight [BW]/week) treated groups; at the end of protocol, the rHuEPO treated rats were subdivided in responders (CRF200) and non-responders (CRF200NR), according to their hematologic response; blood, cellular and tissue studies were performed. The CRF200 group achieved correction of anemia, while the CRF200NR group developed anemia, after an initial response (1st week) to rHuEPO therapy. CRF and CRF200NR groups presented a trend to higher serum CRP levels; CRF200NR showed also high levels of renal inflammatory markers, such as interleukin (IL)-6, IL-1β, nuclear factor kappa B, connective tissue growth factor (CTGF) and transforming growth factor beta 1 (TGF-β1); no changes were found in iron metabolism. Our data suggest that the development of anemia/rHuEPO hyporesponsiveness is associated with a higher systemic and renal inflammatory condition, favoring hypoxia and triggering an increase in renal expression of HIF-1α, TGF-β1 and CTGF that will further aggravate renal fibrosis, which will enhance the inflammatory response, creating a cycle that promotes disease progression. New therapeutic strategies to reduce inflammation in CKD patients could improve the response to rHuEPO therapy and reduce hyporesponsiveness.
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Garrido
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Coimbra, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Fernandes
authors.affiliation: Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB) and Center for Studies in Education, Technologies and Health (CI&DETS), Agrarian School of Viseu, Polytechnic Institute of Viseu, Viseu, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Vala
authors.affiliation: Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
authors.forename: Petronila
authors.initials: P
authors.lastname: Rocha-Pereira
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Elísio
authors.initials: E
authors.lastname: Costa
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Belo
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal. Electronic address: assilva@ff.up.pt.
authors.forename: Alice
authors.initials: A
authors.lastname: Santos-Silva
mesh_terms: D000740:Anemia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C554270:EPO protein, human; D011994:Recombinant Proteins; D004921:Erythropoietin
keywords: Anemia; CTGF; Erythropoietin; Hyporesponsiveness; Inflammation; TGF-β1