Published Online
on August 9, 2004

A more recent version of this article appeared on August 24, 2004

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Submitted on December 16, 2003
Revised on May 13, 2004
Accepted on May 19, 2004

Low-Dose Therapy With the Long-Acting Erythropoietin Analogue Darbepoetin Alpha Persistently Activates Endothelial Akt and Attenuates Progressive Organ Failure

Ferdinand H. Bahlmann MD^*, Rong Song MD, Sascha M. Boehm MS, Michael Mengel MD, Reinhard von Wasielewski MD, Carsten Lindschau PhD, Torsten Kirsch PhD, Kirsten de Groot MD, Robert Laudeley BS, Eva Niemczyk BS, Faikah Güler MD, Jan Menne MD, Hermann Haller MD, and Danilo Fliser MD

From the Division of Nephrology, Department of Internal Medicine (F.H.B., R.S., S.M.B., C.L., T.K., K.d.G., F.G., H.H., D.F.), and Institute of Pathology (M.M., R.v.W.), Hannover Medical School; and Phenos GmbH (R.L., E.N., J.M.), Hannover, Germany.

^* To whom correspondence should be addressed. E-mail: Bahlmann.Ferdinand{at}MH-Hannover.de.

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.

Methods and 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 µg/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.

Key words: apoptosis • erythropoietin • tissue • vasculature • endothelium

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