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 red blood cell (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 concentration, and blood
urea nitrogen. Systemic administration of
pNaKtide, but not
NaKtide (
pNaKtide without the TAT leader sequence) and a scramble "
pNaKtide" (sc-
pNaKtide), led to the normalization of hematocrit, RBC survival, and
plasma protein carbonylation. Administration of the three
peptides had no significant effect on PNx-induced increases in plasma
erythropoietin and blood
urea nitrogen 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 RBC survival.NEW & NOTEWORTHY The
anemia of CKD is multifactorial, and the current treatment based primarily on stimulating bone marrow production of RBCs with
erythropoietin or
erythropoietin analogs is unsatisfactory. In a murine model of CKD that is complicated by
anemia, blockade of Na-K-
ATPase signaling with a specific
peptide (
pNaKtide) ameliorated the
anemia primarily by increasing RBC survival. Should these results be confirmed in patients, this strategy may allow for novel and potentially additive strategies to treat the
anemia of CKD.