Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia

被引：11

作者：

Garrido, Patricia ^{[1
]}

Ribeiro, Sandra ^{[2
]}

Fernandes, Joao ^{[1
,2
]}

Vala, Helena ^{[3
]}

Rocha-Pereira, Petronila ^{[4
]}

Bronze-da-Rocha, Elsa ^{[2
]}

Belo, Luis ^{[2
]}

Costa, Elisio ^{[2
]}

Santos-Silva, Alice ^{[2
]}

Reis, Flavio ^{[1
,5
]}

机构：

[1] Univ Coimbra, Fac Med, Inst Biomed Imaging & Life Sci IBILI, Lab Pharmacol & Expt Therapeut, P-3000548 Coimbra, Portugal

[2] Univ Porto, UCIBIO REQUIMTE, Fac Pharm, Dept Biol Sci,Lab Biochem, P-4050313 Oporto, Portugal

[3] Polytech Inst Viseu, Agrarian Sch Viseu, CITAB, CI&DETS,Ctr Studies Educ & Hlth Technol, P-3504510 Viseu, Portugal

[4] Univ Beira Interior, Res Ctr Hlth Sci, P-6201001 Covilha, Portugal

[5] Univ Coimbra, Inst Biomed Imaging & Life Sci CNC IBILI, Ctr Neurosci & Cell Biol, Res Consortium, P-3000548 Coimbra, Portugal

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2016年 / 17卷 / 01期

关键词：

chronic kidney disease; anemia; resistance to rHuEPO therapy; erythropoiesis; iron metabolism; kidney hypoxia; inflammation and fibrosis; remnant kidney rat model; RED-CELL APLASIA; CHRONIC-RENAL-FAILURE; QUALITY-OF-LIFE; STIMULATING AGENTS; IRON ACCUMULATION; MASS INDEX; HEPCIDIN; PREVALENCE; EXPRESSION; INFLAMMATION;

D O I：

10.3390/ijms17010028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum) protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.

引用

页数：22

共 74 条

[1] Hypoxia-inducible erythropoietin signaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression [J].