Clinical issue

Anemia characterized by low erythrocyte counts and reduced serum erythropoietin (sEPO) is commonly observed in patients with chronic kidney disease (CKD). Anemia decreases the capacity of the blood to efficiently oxygenate the tissues of the body and therefore decreases the patient’s quality of life. Although recombinant human EPO is an approved treatment, this biologic is not effective in certain subsets of CKD patients and also has potential adverse effects. Therefore, the development of erythropoiesis-stimulating agents would offer valuable alternative treatment options. However, there has been a lack of experimental models that accurately represent the EPO-deficiency anemia seen in CKD patients and in which new therapies can be tested.

Results

Deletion of the Epo gene in mice causes embryonic lethality; therefore, to create a new model of EPO-deficient anemia, the authors of this study develop an Epo conditional-knockout mouse by inserting loxP sites into the Epo gene. By crossing mice carrying this floxed Epo allele with mice carrying an inducible Cre transgene, Epo is postnatally ablated. When Cre activity is induced in the new strain, Epo expression is substantially reduced. These mice develop a chronic, normocytic and normochromic anemia, and display low sEPO levels, a phenotype that resembles the clinical symptoms of patients that suffer from anemia caused by CKD. Surprisingly, although Epo conditional-knockout mice display lower hematocrit and reduced sEPO levels compared with wild-type mice, their rate of recovery following an induced acute hypoxic stimulus is similar. This suggests that there are other pathways that can compensate for the loss of EPO during hypoxic stress.

Implications and future directions

The Epo conditional-knockout mouse model will provide a tool for preclinical studies of EPO-deficiency anemia caused by CKD. In addition, because these animals do not develop the inflammation or uremia observed in CKD patients, this model will allow the study of erythropoiesis in an EPO-limiting environment in the absence of secondary complications. Furthermore, analyzing responses of these mice to hypoxic stress has the potential to uncover new erythropoiesis-regulating mechanisms that are masked by EPO in currently used models of anemia. Finally, this model will allow investigation of potential roles of EPO outside the erythropoietic system