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Glutaraldehyde erythropoietin protects kidney in ischaemia/reperfusion injury without increasing red blood cell production
Author(s) -
Chattong S,
Tanamai J,
Kiatsomchai P,
Nakatsu M,
Sereemaspun A,
Pimpha N,
Praditpornsilpa K,
Rojanathanes R,
Sethpakadee A,
Tungsanga K,
EiamOng S,
Manotham K
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02123.x
Subject(s) - erythropoietin , erythropoiesis , erythropoietin receptor , cytoprotection , in vivo , medicine , kidney , pharmacology , apoptosis , red blood cell , chemistry , anemia , biochemistry , biology , oxidative stress , microbiology and biotechnology
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 P 19 and HEK 293 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 IL 3 RB / EPOR heterotrimeric receptor and ameliorated cellular apoptosis via the activation of Bcl ‐2. Notably, Bcl ‐2 activation was suppressed by the JAK 2 inhibitor, tyrphostin AG 490. 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.