Hypertension and nephrology

[Incorporation of ortho- and meta-tyrosine into cellular proteins leads to erythropoietin-resistance]

MIKOLÁS Esztella Zsóka1, KUN Szilárd1, LACZY Boglárka1, MOLNÁR Gergő Attila1, SÉLLEY Eszter1, KŐSZEGI Tamás2, WITTMANN István1

FEBRUARY 10, 2016

Hypertension and nephrology - 2016;20(01)

[Introduction: Erythropoietin (EPO) is a glycoprotein hormone, which is responsible for the proliferation and differentiation of erythroid cell lines. Since it is widely used as the treatment of renal anaemia, EPO-resistance is a common concern. Aims: We aimed to perform in vitro experiments to investigate a possible mechanism of EPO-hyporesponsiveness. Methods: We used a factor dependent erythroblast cell line (TF-1). Two independent observers calculated cell counts simultaneously on day 1; 2 and 3 in Bürker cell counting chambers. Colorimetric method was used to measure protein concentrations. Measurement of protein-bound para-, ortho- and meta-tyrosine was performed with reverse phase high performance liquid chromatography with fluorescence detection. We determined ERK and STAT5 activation using Western blot method. Results: In case of ortho- and meta-tyrosine pretreated cells time-dependent, EPOinduced proliferative activity was decreased compared to the 1.7 fold elevation of cell counts seen in para-tyrosine cultured cells. Protein concentration of ortho- and metatyrosine treated samples was significantly lower than control cells on the third day. Addition of para-tyrosine reclaimed EPO-sensitivity. Erythroblasts treated with orthoor meta-tyrosine contained lower concentrations of protein-bound para-tyrosine with higher ortho- and meta-tyrosine content. EPO dependent activation of ERK and STAT5 could be inhibited by ortho- or meta-tyrosine treatment. Conclusions: Elevated level of protein-bound ortho- and meta-tyrosine in erythroblasts can result in the pathological modification of intracellular signaling, leading to EPOhyporesponsiveness.]


  1. Pécsi Tudományegyetem, Általános Orvostudományi Kar, II. Sz. Belgyógyászati Klinika és Nephrológiai Centrum, Pécs
  2. Pécsi Tudományegyetem, Általános Orvostudományi Kar, Laboratóriumi Medicina Intézet, Pécs



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