Erythropoietin (EPO) induces erythrocytosis by suppressing erythroid progenitor cell apoptosis through the JAK-STAT pathway. Since apoptosis contributes to cisplatin (CP) nephrotoxicity, and EPO receptors are expressed in kidneys, we examined the role of antiapoptosis in recombinant human epoetin alfa (rHuEPO)-mediated renal protection. In human renal proximal tubular epithelial (RPTE) cells, rHuEPO, but not inactive rHuEPO (I-rHuEPO) whose receptor binding sites are mutated, caused a significant reduction in CP-induced apoptosis. rHuEPO, but not I-rHuEPO, increased STAT5 and Akt/PKB phosphorylation, demonstrating functional EPOR expression on RPTE cells. Furthermore, JAK2 inhibitor, tyrphostin AG490 attenuated rHuEPO protection, suggesting a role of JAK-STAT pathway. In the rats, administration of rHuEPO, but not I-rHuEPO, prior to CP, significantly increased Hct and reduced CP-induced increase in serum creatinine (S Cr). S Cr (mean±SE) on day 4 was 3.4±0.3 mg/dl in the CP group, 1.9±0.3 mg/dl in the CP+rHuEPO group and 3.5±0.4 mg/dl in the CP+I-rHuEPO group. Similarly, darbepoetin alfa (DA), a hyperglycosylated analog of rHuEPO, when injected prior to CP, significantly increased Hct and reduced S Cr. Renal clearance studies based on GFR and RBF confirmed the renal protection by DA against CP along with suppression of tubular apoptosis and necrosis. The equalization of Hct levels by venesection did not abrogate DA protection. Administration of DA 48-hrs after CP also conferred significant renal protection. Our experiments confirm a role for erythropoiesis stimulating proteins (ESP) including the new analog DA in limiting CP-nephrotoxicity and suggest that anti-apoptosis via the EPO-EPOR interaction is an important mechanism for renal protection.