Darbepoetin-␣ treatment enhances glomerular regenerative process in the Thy-1 glomerulonephritis model. Am J Physiol Renal Physiol 299: F1278-F1287, 2010. First published September 8, 2010 doi:10.1152/ajprenal.00343.2009.-Recent studies have demonstrated that erythropoietin (EPO) and its analogs induce cytoprotective effects on many nonerythroid cells. In this study, we examined whether darbepoetin-␣ might prevent glomerular lesions in the Thy-1.1 model of glomerulonephritis (Thy-1-GN). GN was induced in Wistar rats by a single injection of monoclonal anti-Thy-1.1 antibody. Rats were killed at 24 h, 72 h, 7 days, 10 days, or 15 days after antibody injection. Kidneys were removed for histological analysis, and proteinuria was measured. Because at day 7 the maximal degree of renal damage and proteinuria was found, the effect of darbepoetin-␣ was tested at day 7 and two different protocols of administration were used; After anti-Thy-1.1 injection, rats received two doses of darbepoetin-␣ or vehicle at days 0 and 4 or at days 4 and 6. At day 7, proteinuria, plasma creatinine concentration, and renal morphology analysis were performed. Also, ␣-actin, desmin, caspase-3, and Ki67 protein expression were evaluated by immunohistochemistry. Our results showed that in both protocols of administration, darbepoetin-␣ treatment decreased proteinuria in Thy-1-GN rats and this effect correlated with the improvement in renal morphology. Glomerular lesions, ␣-actin, and caspase-3 protein expression, observed in most glomeruli of Thy-1-GN rats, were significantly reduced in darbepoetin-␣-treated rats, while cell proliferation was significantly enhanced. The results indicate that darbepoetin-␣ treatment promotes glomerular recovery. erythropoietin analog; cytoprotective effects; glomerular regeneration ERYTHROPOIETIN (EPO) has been described as a hematopoietic cytokine required for the proliferation and differentiation of erythroid progenitor cells regulating the level of circulating red blood cells (4). However, it has been reported that EPO receptors (EPORs) are also expressed in nonerythroid cells (neurons, endothelial cells, cardiomyocytes, renal tubular cells, podocytes, and mesangial cells) which can respond to EPO treatment (17,18,22,24,27).Therefore, it seems that the therapeutic benefits of EPO treatment on nonhematopoietic tissues are not only the result of the correction of anemia-related tissue hypoxia, suggesting that there are further molecular pathways involved (5,7,9,23,25,26).