We have previously demonstrated that the Na/K-ATPase signaling-mediated oxidant amplification loop contributes to experimental uremic cardiomyopathy and anemia induced by 5/6th partial nephrectomy (PNx). This process can be ameliorated by systemic administration of the peptide, pNaKtide, which was designed to block this oxidant amplification loop. The present study demonstrated that the PNx induced anemia is characterized by marked decreases in RBC survival as assessed by biotinylated RBC clearance and eryptosis as assessed by annexin V binding. No significant change in iron homeostasis was observed. Examination of plasma samples demonstrated that PNx induced significant increases in systemic oxidant stress as assessed by protein carbonylation, plasma erythropoietin (EPO) concentration, and BUN. Systemic administration of pNaKtide, but not by NaKtide (pNaKtide without TAT leader sequence) and a scramble "pNaKtide" (sc-pNaKtide), led to the normalization of hematocrit, RBC survival, plasma protein carbonylation. Administration of the three peptides has no significant effect on PNx-induced increases in plasma EPO and BUN, without notable changes in iron metabolism. These data indicate that blockage of the Na/K-ATPase signaling-mediated oxidant amplification loop ameliorates the anemia of experimental renal failure by increasing the RBC survival.