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Pathological and molecular mechanisms underlying resistance to recombinant human erythropoietin therapy in the remnant kidney rat model of chronic kidney disease associated anemia

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dc.contributor.authorRibeiro, Sandra
dc.contributor.authorGarrido, Patrícia
dc.contributor.authorFernandes, João
dc.contributor.authorVala, Helena
dc.contributor.authorRocha-Pereira, Petronila
dc.contributor.authorCosta, Elísio
dc.contributor.authorBelo, Luís
dc.contributor.authorReis, Flávio
dc.contributor.authorSantos-Silva, Alice
dc.date.accessioned2016-04-13T09:20:24Z
dc.date.available2016-04-13T09:20:24Z
dc.date.issued2016
dc.description.abstractAnemia 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 IU/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.pt_PT
dc.identifier.citationRibeiro S, Garrido P, Fernandes J, Vala H, Rocha-Pereira P, Costa E, Belo L, Reis F, Santos-Silva A (2016). Pathological and molecular mechanisms underlying resistance to recombinant human erythropoietin therapy in the remnant kidney rat model of chronic kidney disease associated anemia. Biochimie. 125: 150-162pt_PT
dc.identifier.doi10.1016/j.biochi.2016.03.012pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.19/3156
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationThis study was conducted with financial support from Portuguese Foundation for Science and Technology (FCT)/MEC through national funds and co-financed by COMPETE-FEDER (PTDC/SAUTOX/ 114253/2009, Pest/C/SAU/3282/2013), by FEDER under the Partnership Agreement PT2020 (UID/MULTI/04378/2013 e POCI/ 01/0145/FERDER/007728, UID/NEU/04539/2013, UID/AGR/04033/ 2013 e POCI-01-0145-FEDER-006958) and by POPH/FSE (SFRH/BD/ 61020/2009, SFRH/BD/79875/2011 and SFRH/BPD/81968/2011).We would like to thank Jos e Sereno, Filipa Melo and Sara Nunes for all the technical support, and also to CI&DETS and CITABpt_PT
dc.subjectAnemiapt_PT
dc.subjectTGF-b1pt_PT
dc.subjectCTGFpt_PT
dc.subjectErythropoietinpt_PT
dc.subjectHyporesponsivenesspt_PT
dc.subjectInflammationpt_PT
dc.titlePathological and molecular mechanisms underlying resistance to recombinant human erythropoietin therapy in the remnant kidney rat model of chronic kidney disease associated anemiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage162pt_PT
oaire.citation.startPage150pt_PT
oaire.citation.titleBiochimiept_PT
oaire.citation.volume125pt_PT
person.familyNameVala Correia
person.givenNameHelena Maria
person.identifier.ciencia-id7A1E-E85E-FFA4
person.identifier.orcid0000-0001-6829-4867
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationcdc3d2e2-df06-40ed-8900-1ecbc8a06c8a
relation.isAuthorOfPublication.latestForDiscoverycdc3d2e2-df06-40ed-8900-1ecbc8a06c8a

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