NDT Advance Access published online on October 25, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm707
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Carnitine-Mediated Improved Response to Erythropoetin Involves Induction of Haem Coxygenase-1: Studies in Humans and in an Animal Model
1 Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Italy 2 Department of Nutrition, University of California, Davis, USA 3 Division of Nephrology 2, University of Padova, Italy 4 Division of Nephrology 1, University of Padova, Italy 5 Nephrology and Dialysis Units of Bolzano, Italy 6 Nephrology and Dialysis Units of Piove di Sacco, Italy 7 Nephrology and Dialysis Units of Papardo-Messina, Italy 8 Department of Biomedical Sciences, CNR Unit for Muscle Biology and Pathophysiology, University of Padova, Italy
Correspondence and offprint requests to: Correspondence and offprint requests to: Lorenzo Calò, Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. Tel: +39-049-8218701/8212279; Fax: +39-049-8754179; E-mail: renzcalo{at}unipd.it
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Abstract |
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Background. Carnitine improves erythropoetin (EPO) response and anaemia in haemodialysis patients (HD); however, the mechanism(s) responsible remain unidentified. We have reported that carnitine induces haem oxygenase (HO)-1, which is an antioxidant and antiapoptotic that acts via pathways shared with EPO. Therefore carnitine's effect on these pathways may account for the improved EPO response. This study evaluates carnitine's effect on protein expression of HO-1 in unexplained EPO resistant HD. Carnitine's effect was assessed by HO-1 expression in patients and compared to its antiapoptotic effect via HO-1 induction in a rat model of carnitine-treated heart failure.
Methods. Unexplained EPO resistant HD mononuclear cell HO-1 and rat gastrocnemious muscle HO-1 and Bcl-2 protein expression were evaluated by western blot.
Results. HD's haemoglobin (Hb) and haematocrit (Ht) were not different before carnitine treatment: 8.8 ± 0.4 mg/dl versus 8.98 ± 0.13 and 30.20% ± 0.84 versus 30.72 ± 1.14, respectively. Carnitine increased HO-1, Hb and Ht compared with patients not treated with carnitine: 2.40 ± 0.58 versus 1.49 ± 0.41, P = 0.02; 11.22 ± 0.54 versus 8.90 ± 0.15, P < 0.0001; 32.72 ± 1.77 versus 30.66 ± 0.43, P = 0.035, respectively. Carnitine-treated HD's HO-1 significantly correlated with haemoglobin. HO-1 and Bcl-2 protein levels in untreated heart failure rat's gastrocnemious muscle were reduced when compared with controls: 3.41 ± 0.49 versus 5.32 ± 0.38 and 0.69 ± 0.11 versus 1.65 ± 0.37, respectively, but were higher in carnitine-treated heart failure rats: 4.8 ± 0.32 versus 3.41 ± 0.49, P < 0.0002 and 1.09 ± 0.08 versus 0.69 ± 0.11, P = 0.0007, respectively.
Conclusions. These results are consistent with an involvement of HO-1 in carnitine's effect on erythropoiesis. The initial signals or effectors responsible for carnitine's effect remain to be identified.
Keywords: anaemia; apoptosis; carnitine; dialysis; erythropoietin; haem oxygenase-1
Received for publication: 30. 5.07
Accepted in revised form: 11. 9.07