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Objective: 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 longacting recombinant human erythropoietin analogue darbepoetin alpha protects vascular endothelium in a classical remnant kidney rat model (5/6 nephrectomy) characterized by severe endothelial damage, progressive vascular sclerosis, and ischemia-induced tissue fibrosis. Methods: Using a parallel group study design we randomly assigned animals after nephrectomy either to treatment with saline (n = 36) or 0.1 µg/kg body weight darbepoetin (n = 24) subcutaneously once weekly. We monitored hematocrit, blood pressure and serum creatinine regulary, and obtained renal tissue 6 weeks after nephrectomy for morphological and immunohistochemical analysis. Results: Darbepoetin-treated animals had significantly improved survival compared to saline-treated controls (63% vs. 33%; p < 0.05; Fig. 1) 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), that 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 through persistent stimulation of the prosurvival Akt signaling pathway. The use of recombinant human erythropoietin or analogues may have utility in preventing ischemia-related progressive vascular injury and organ failure. [ABSTRACT FROM AUTHOR]