Az erythropoetin szénhidrát-anyagcserére kifejtett hatása és az erythropoetin-rezisztencia

Abstract

The glycoprotein hormone erythropoietin (EPO) was first identified as the key regulator of red blood cell differentiation and maturation. EPO is synthesized by the kidney peritubular interstitial cells; typically, the lack of EPO production associated with chronic kidney disease results in hypoproliferative anemia. While much of our understanding of the role of EPO is related to promoting erythropoiesis, accumulating evidence demonstrates that EPO is more ubiquitous possessing non-erythroid biological actions, thus affecting different cellular functions in multiple cell systems. EPO-receptor (EPO-R) is a member of the cytokine-receptor superfamily involving the activation of downstream effectors via PKB/Akt, p44/42 ERK, and JAK/STAT pathways. Expression of EPO-R has been demonstrated in numerous cell types in the nervous system e.g., brain capillary endothelial cells, hippocampal and cortical neurons, human neurons, astrocytes, and microglia as well as in the pancreatic islets [1][2][3][4][5]. It has been reported that EPO inhibited apoptosis in breast cancer cells via the PKB/Akt pathway [6]. Administration of EPO protected neurons against cell death and promoted post-stroke recovery in experimental models of stroke and cerebral ischemia. It has been shown that EPO reduced the accumulation of lipids in foam cells and suppressed the progression of atherosclerosis [7]. Hojman et al. showed that EPO led to an increased fat oxidation in striated muscles and prevented diet-induced obesity [8]. Based on unpublished data, we found that introduction of r-hu-EPO therapy markedly decreased fructosamine levels in two patients with type 2 diabetes mellitus within the 2-4 months after post-injection, indicative of better glycemic-status [fructosamine (μmol/l) 372 to 321 and 464 to 428]. We concluded, that introduction of EPO-therapy ameliorates glycaemic state. Although consequences of sustained EPO treatment are well described, to date, results have been lacking on the acute glucose lowering effect of EPO. The major aim of present study was to investigate the acute changes in blood glucose levels after EPO administration in vivo. Moreover, we purposed to determine in adipocytes the effect of EPO on cellular glucose uptake and intracellular signaling events under normal and high glucose conditions, as well as the effect of EPO on glucose transporter 4 (GLUT4) trafficking to the plasma membrane using 3T3-L1 cells. Renal anaemia is present in patients suffering in chronic kidney disease (CKD), resulting in the impairment of quality of life. Approximately 15 % of the recombinant-human-EPO (r-hu-EPO) receiving subjects are hyporesponsive [9]. Several possible pathomechanisms are discussed, such as iron deficiency, use of angiotensin converting enzyme inhibitors, uremic toxins, insufficient dialysis, hyperparathyroidism or malignancy. Ehrlich observed in 1906 the phenomenon, known as concomitant tumor resistance, where a tumor-bearing host inhibits the growth of secondary tumor implants or metastasis. Ruggiero et al. identified the active serum fraction responsible for this phenomenon containing a mixture of the three isoforms of tyrosine. According to their in vitro and in vivo studies ortho- and meta-tyrosine inhibits tumor growth in a dose dependent manner. Using immunoblot analysis, they found impaired ERK and STAT3 activation in the presence of meta-tyrosine [10][11]. Tyrosine is a non-essential amino-acid, physiologically formed from phenylalanin by enzimatic hydroxylation. When excessive amount of hydroxyl radical is present, L-phenylalanine is converted into meta-tyrosine and ortho-tyrosine, besides the enzymatic formation of the physiological isomer, para-tyrosine. According to our present knowledge, beside the acute, cytotoxic effect of the two tyrosine isomers, a long-term effect is possible. Specifically, the incorporation of ortho- and meta-tyrosine into cellular proteins can lead to the disturbance of cellular signaling. Based on these observations we hypothesized, that integration of meta- and ortho-tyrosine into cellular proteins may result in the alteration of signal transduction, leading to EPO-hyporesponsiveness.