Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion.
Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
Department of Experimental Medicine and Nephrology, William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine, Queen Mary College, University of London, United Kingdom. edsharps@doctors.org.uk
Edward J
EJ
Sharples
Nimesh
N
Patel
Paul
P
Brown
Keith
K
Stewart
Helder
H
Mota-Philipe
Michael
M
Sheaff
Julius
J
Kieswich
David
D
Allen
Steven
S
Harwood
Martin
M
Raftery
Christoph
C
Thiemermann
Muhammad M
MM
Yaqoob
D000818:Animals; D017209:Apoptosis; D001798:Blood Proteins / Q000494:pharmacology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control
D001798:Blood Proteins; D061945:Caspase Inhibitors; D011518:Proto-Oncogene Proteins; D004921:Erythropoietin; D003404:Creatinine; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases