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

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Ribeiro, S (Author) Other; Garrido, P (Author) Other; Fernandes, J (Author) Other; Vala, H (Author) Other; Rocha Pereira, P (Author) Other; Costa, E (Author) FFUP; Belo, L (Author) FFUP; Reis, F (Author) Other; Alice Santos Silva (Author) FFUP

Journal

The Journal is awaiting validation by the Administrative Services.

Title: BIOCHIMIE

Vol. 125

Pages: 150-162

ISSN: 0300-9084

Indexing

ISI Web of Knowledge - 10 Citations

Scopus - 10 Citations

Other information

Authenticus ID: P-00K-E69

DOI: 10.1016/j.biochi.2016.03.012

Abstract (EN): 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 [BM/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-1 beta, nuclear factor kappa B, connective tissue growth factor (CTGF) and transforming growth factor beta 1 (TGF-beta 1); 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-1 alpha, TGF-beta 1 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13