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Glutaraldehyde erythropoietin protects kidney in ischaemia/reperfusion injury without increasing red blood cell production.

Abstract：

BACKGROUND AND PURPOSE:Recombinant human erythropoietin (rHuEPO) is currently the mainstay of renal anaemia treatment. Recently, rHuEPO has been shown to provide pleiotrophic tissue protection in various pathological conditions. However, the benefits of rHuEPO beyond anaemia treatment are limited because it increases red blood cell mass. Carbamylated erythropoietin (CEPO) is the first rHuEPO derivative that lacks erythropoietic activity but retains tissue protection properties. Since carbamylation targets lysine residues on rHuEPo, we hypothesized that targeted lysine modifications of rHuEPO may result in a novel non-erythropoietic erythropoietin. EXPERIMENTAL APPROACH:rHuEPO was subjected to various targeted lysine modifications. In vitro cytoprotection and apoptosis were evaluated using P19 and HEK293 cells. In vivo erythropoiesis was performed by administering the derivatives to animals for 2 weeks. Renoprotection was tested on an ischaemia/reperfusion (I/R) model. KEY RESULTS:We synthesized a novel derivative, a glutaraldehyde erythropoietin (GEPO). This construct abolished in vivo erythropoiesis. Biochemical characterization showed that GEPO was more electrostatically negative than rHuEPO. Immunoprecipitation experiments revealed that GEPO bound to the IL3RB/EPOR heterotrimeric receptor and ameliorated cellular apoptosis via the activation of Bcl-2. Notably, Bcl-2 activation was suppressed by the JAK2 inhibitor, tyrphostin AG490. In vivo experiments showed that GEPO also ameliorated kidney damage due to I/R injury both functionally and histologically. CONCLUSIONS AND IMPLICATIONS:Herein, we describe a novel lysine-modified rHuEPO, glutaradehyde-EPO (GEPO), obtained from a simple reaction. This derivative has no erythropoietic properties but retains cell-protective characteristics both in vitro and in vivo, with promise for future use as an adjunctive treatment of kidney disease.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Chattong S,Tanamai J,Kiatsomchai P,Nakatsu M,Sereemaspun A,Pimpha N,Praditpornsilpa K,Rojanathanes R,Sethpakadee A,Tungsanga K,Eiam-Ong S,Manotham K

doi

10.1111/j.1476-5381.2012.02123.x

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

189-99

issue

eissn

0007-1188

issn

1476-5381

journal_volume

168

pub_type

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Glutaraldehyde erythropoietin protects kidney in ischaemia/reperfusion injury without increasing red blood cell production.