Submitted on May 29, 2008
Revised on September 2, 2008
Accepted on September 21, 2008
The JAK2/Y343/STAT5 Signaling Axis is Required for Erythropoietin-Mediated Protection against Ischemic Injury in Primary Renal Tubular Epithelial Cells
Anne C Breggia1, Don W. Wojchowski, and Jonathan Himmelfarb2*
1 Maine Medical Center Research Institute
2 U Washington
* To whom correspondence should be addressed. E-mail: himmej{at}u.washington.edu.
Erythropoietin has emerged as a potential therapy for the treatment of ischemic tissue injury. In erythroid cells, the JAK2/Y343/STAT5 signaling axis has been shown to be necessary for stress but not steady-state erythropoiesis. The requirement for STAT5 activation in erythropoietin mediated protection from ischemic injury has not been well studied. To answer this question, we induced reproducible necrotic ischemic injury in primary mouse renal tubular epithelial (RTEC) cells in vitro. Using RTEC from erythropoietin receptor mutant mice with differential STAT5 signaling capabilities we have demonstrated first, that EPO administration either before or during injury significantly protects against mild-moderate but not severe necrotic cell death; and second, the JAK2/Y343/STAT5 signaling axis is required for protection against ischemic injury in primary mouse renal tubular epithelial cells. In addition, we have identified Pim-3, a pro survival STAT5 target gene, as responsive to EPO in the non injured kidney both in vitro and in vivo.
