NDT Advance Access originally published online on July 2, 2008
Nephrology Dialysis Transplantation 2008 23(9):3035-3036; doi:10.1093/ndt/gfn315
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EPO induces rise in serum ADMA but does not prevent the increase in NO release: the likely involvement of HO-1
E-mail: renzcalo{at}unipd.itSir,
We read with great interest Desai and co-workers’ report in the May issue of Nephrology Dialysis Transplantation that in spite of elevating serum asymmetric dimethylarginine (ADMA), erythropoietin (EPO) in animals did not compromise NO production as shown by the increased urinary NO metabolites [1]. These authors found a chronic upregulation of kidney NOS1 and NOS2 upon EPO treatment and concluded that a compensatory increase in NO release overcame the increased ADMA level induced by EPO.
We would like to suggest that results from our study of EPO effects in chronic haemodialysis (CH) patients [2] provide additional support for Desai and co-workers’ conclusions and add a mechanism for the effect of EPO on NO availability. CH patients are widely recognized as having increased oxidative stress and reduced NO availability [3]. When this CH cohort underwent EPO treatment (epoetin 
at the dose of 50–100 UI/kg, three times/week aiming towards a target haemoglobin of 11 g/dl and then adjusted to maintain it), EPO increased mononuclear cell HO-1 gene expression via a possible direct effect of EPO [2]. HO-1 is a phase II enzyme induced by oxidative stress that possesses potent antioxidant, antiapoptotic and anti-inflammatory activities [4,5]. HO-1 expression in response to oxidative stress is transcriptionally regulated by the phosphatidylinositol 3-kinase (PI3K)/Akt pathway [6]. EPO-mediated attenuation of cell death in response to oxidative stress has been shown to be dependent on JAK2 signalling and PI3K-mediated phosphorylation of Akt which, once triggered, activates multiple antiapoptotic effects [7]. Given that both EPO and HO-1 antiapoptotic effects occur via the PI3K/Akt pathway, HO-1 probably plays an important role in the antiapoptotic effect of EPO. Moreover, there is a close relationship between HO-1 and NO production as the decreased eNOS expression and endothelial dysfunction seen after exposure to proinflammatory factors such as oxidated LDL and TNF- were restored by HO-1 overexpression [8]. Further, increased HO-1 expression in diabetic rats boosted eNOS and normalized vascular relaxation while it differentially decreased iNOS protein levels [9].
In conclusion, our study showing increased HO-1 in CH patients treated with EPO supports Desai and co-workers’ conclusions that a compensatory increase of NO production capacity occurs upon EPO treatment and this then overcomes the increased ADMA level induced by EPO.
Conflict of interest statement. None declared.
1 Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Padova Italy 2 Department of Nutrition, University of California, Davis, CA, USA
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