Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure.
BACKGROUND
The hematopoietic cytokine erythropoietin has cytoprotective effects in endothelial cells in vitro that are mediated through direct activation of the pro-survival Akt tyrosine kinase signaling pathway. We tested the hypothesis that low-dose therapy with the long-acting recombinant human erythropoietin analogue darbepoetin alpha protects vascular endothelium in vivo in a classic remnant kidney rat model characterized by severe endothelial damage, progressive vascular sclerosis, and ischemia-induced tissue fibrosis.


RESULTS
Using a parallel group study design, we randomly assigned animals after 5/6 nephrectomy to treatment with either saline (n=36) or 0.1 microg/kg body wt darbepoetin (n=24) subcutaneously once weekly. We monitored hematocrit, blood pressure, and serum creatinine regularly and obtained renal tissue 6 weeks after nephrectomy for morphological and immunohistochemical analysis. Darbepoetin-treated animals had significantly improved survival compared with saline-treated controls (63% versus 33%; P<0.05), although hematocrit levels were similar in both groups. Darbepoetin treatment ameliorated endothelial damage; attenuated the composite tissue injury score (saline 1.9+/-0.4; darbepoetin 0.4+/-0.2; P<0.001), which included vascular sclerosis, glomerulosclerosis, and tubulointerstitial damage; and preserved renal function. We found persistent activation of the pro-survival Akt signaling pathway in endothelial and epithelial glomerular cells in darbepoetin-treated animals, accompanied by a significant reduction of apoptotic cell death in renal tissue.


CONCLUSIONS
Low-dose darbepoetin treatment confers vascular and tissue protection that is associated with persistent stimulation of the pro-survival Akt signaling pathway. The use of recombinant human erythropoietin or analogues may have utility in preventing ischemia-related progressive vascular injury and organ failure.
Department of Internal Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. Bahlmann.Ferdinand@MH-Hannover.de
Ferdinand H
FH
Bahlmann
Rong
R
Song
Sascha M
SM
Boehm
Michael
M
Mengel
Reinhard
R
von Wasielewski
Carsten
C
Lindschau
Torsten
T
Kirsch
Kirsten
K
de Groot
Robert
R
Laudeley
Eva
E
Niemczyk
Faikah
F
Güler
Jan
J
Menne
Hermann
H
Haller
Danilo
D
Fliser
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D006400:Hematocrit; D019650:Hematopoietic Stem Cell Mobilization; D006977:Hypertension, Renal / Q000209:etiology / Q000503:physiopathology; D007511:Ischemia / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply; D015993:Life Tables; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000209:etiology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D011518:Proto-Oncogene Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt