Delayed treatment with erythropoietin attenuates renal fibrosis in mouse model of unilateral ureteral obstruction

Objectives Erythropoietin (EPO) exerts tissue‐protective effects on various organs including the kidney. However, the effects of EPO on established renal fibrosis remain unclear. In this study, we aimed to examine the therapeutic potential of EPO against established renal fibrosis. Methods Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) and the mice were treated with recombinant human EPO (rhEPO) daily during 7 and 13 days after UUO. The degrees of renal fibrosis, myofibroblast accumulation, and macrophage infiltration; the mRNA expression levels of transforming growth factor (TGF)‐β1 and α1(I) collagen; and the protein levels of Kelch‐like ECH‐associated protein 1 (Keap1) and nuclear NF‐E2‐related factor 2 (Nrf2) in the kidneys were assessed on day 14 after UUO. Results Treatment with rhEPO significantly decreased fibrosis, myofibroblast accumulation, and α1(I) collagen mRNA expression, but it did not significantly affect TGF‐β1 mRNA expression. Although treatment with rhEPO did not significantly affect the total number of interstitial macrophages, it significantly decreased the number of CD86‐positive cells (M1 macrophages), while significantly increased the number of CD206‐positive cells (M2 macrophages) in the interstitium. Treatment with rhEPO did not affect the Keap1/Nrf2 protein level or the peripheral blood hematocrit value. Conclusions These results indicate for the first time that EPO exerts antifibrotic effects against the evolution of established renal fibrosis, possibly by influencing the polarization of infiltrating macrophages.