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Recombinant human erythropoietin (rHuEPO) has emerged as a new renoprotective agent against various acute kidney injuries. Experience with rHuEPO in chronic kidney injuries is so far limited and conflicting results were obtained. In the present study, we addressed to evaluate the long-term renal effects of rHuEPO in diabetic nephropathy (DN) of rats in relation to novel hypoxia theory and endogenous EPO secretion. We compared rHuEPO to a standard drug, losartan (LSR), and the possibility of add-on therapy was also tested. Thirty-four male SpragueDawley rats were randomly divided into five groups: control-naïve group, untreated diabetic group, EPOtreated diabetic group (150 U/kg, S.C., TIW), LSR-treated diabetic group (5 mg/kg/day), and EPO-LSRtreated diabetic group. Drug treatment was started one week after streptozotocin (STZ) injection and continued for twenty-eight weeks. STZ-treated diabetic rats developed progressive albuminuria, renal dysfunction, and significant glomerular change 28 weeks after induction of diabetes. Chronic administration of rHuEPO alone or in combination with LSR to the STZ-induced diabetic rat did not show beneficial effect on DN evolution, inspite of improving diabetic-renal hypoxia. The best beneficial effect on DN evolution was obtained by LSR sole therapy based on renal function evaluation, albuminu-

LONG-TERM STUDY OF ERYTHROPOIETIN, LOSARTAN, AND COMBINATION IN STREPT- OZOTOCIN-INDUCED DIABETIC RATS